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Effects of cerebellar vermal lesions on species-specific fear responses, neophobia, and taste-aversion learning in rats

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Abstract

The cerebellar vermis has extensive anatomical connections with many brain stem and forebrain structures which have been implicated in emotional or affective behavior. Previous reports indicate that lesions of the vermis in a variety of experimental animals result in altered emotional behavior. The studies reported here attempted to clarify the nature of the change in emotional behavior following vermal lesions in rats by testing the animals in a variety of fear-eliciting situations. As compared with controls, vermal-lesioned rats froze less in the presence of a cat and showed fewer signs of fear in an open field. However, their responses to footshock did not differ fundamentally from controls. They recovered more quickly than controls from the neophobic response to a novel taste but showed robust taste-aversion learning. The results are discussed in terms of the role of the cerebellum in the modulation of fear-related behaviors and in terms of similarities and differences with the effects of amygdala lesions. The results expand the body of data implicating the cerebellum in the modulation of complex motivational behavior.

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... Taming effects have been reported in cats and monkeys upon cerebellar vermal lesions, and many fear-related defensive behaviours have been shown to be attenuated by lesions of the vermis or fastigial nucleus (Berman, Berman & Prescott, 1974;Supple, Leaton & Fanselow, 1987;Bemtson & Torello, 1982). Indeed, it has been suggested that the anterior vermis, in particular, is involved specifically in the expression of the classically conditioned bradycardia (Supple & Kapp, 1988;Supple, Archer & Kapp, 1989). ...
... With respect to a cerebellar involvement in affective behaviour, lesions of the vermis but not hemispheres, impair a variety of species-specific defensive behaviours in rats (Supple, Cranney & Leaton, 1988;Supple, Leaton & Fanselow, 1987;, findings consistent with reports in the monkey (Berman, Berman & Prescott, 1974;Peters & Morgan, 1971). Similar involvement of the midline cerebellum and hypothalamus in such behaviours are supported by a rich neuroanatomical network that includes connections between the dorsomedial and lateral hypothalamus and the anterior vermis in a number of species including the rabbit (Dietrichs & Haines, 1989) and also by the fact that these two regions are functionally interactive (Supple, 1993). ...
... It is clear that the cerebellar vermis is implicated in the mediation of certain behaviours (See chapter 1, Introduction chapter 4; Bemston & Torello, 1982;Supple et al., 1987;1988). Stimulation of the midline vermis evokes or potentiates different fear related-somatomotor responses (Albert et al., 1985) whereas lesions of lobules III, IV and V of the anterior and lobules VI, VII and VIII of the posterior vermis blocks the hyperdefensiveness induced by lesions of the VMH, attenuates mouse killing and reduces unconditioned freezing in rats (Supple, Cranney & Leaton, 1988). ...
Thesis
The aim of the present study was to ascertain possible roles for the posterior cerebellar vermis in cardiovascular control using the anaesthetised, paralysed and artificially ventilated rabbit. The cortex of lobule IXb was stimulated both electrically and chemically and the effects of removal of lobules VI, VII and IX on the cardiorespiratory responses evoked from defensive behaviour related structures were observed. Arterial blood pressure, heart rate, femoral and renal vascular blood flow, and phrenic and renal nerve activities were routinely measured. Removal of lobule IX resulted in an increase in the sensitivity of the baroreceptor reflex response to a pressor challenge induced by intraluminal balloon inflations in the descending aorta. The increase in baroreflex gain was still evident when the experiments were carried out under β1-receptor blockade, the cell bodies in only lobule IXb were lesioned and whether the gain was calculated using R-R intervals derived from the heart rate or absolute R-R intervals. Stimulation of the HDA or PAG and ACe results in cardiorespiratory responses that are synonymous with those which occur in "fight or flight" and "playing dead" behaviours, respectively. Removal of lobule IX, but not lobules VI and VII, resulted in attenuated HDA, PAG and ACe evoked cardiovascular responses. On the other hand, simultaneous stimulation of lobule IXb with either of these structures resulted in facilitated "cardiovascular defence responses". Indeed, chemical activation of neurons in the HDA, PAG, ACe and lobule IXb identified the structure related nature of these cerebellar-midbrain/forebrain interactions. The cardiovascular effects elicited from the HDA or ACe and lobule IXb were vastly attenuated when cell bodies in the ipsilateral lateral parabrachial nucleus (LPBN) were lesioned with the excitotoxin kainic acid. Neurons in lobule IX demonstrated their ability to receive baroreceptor and hypothalamic inputs upon single or paired-pulse stimulation of the ipsilateral aortic nerve and hypothalamic defence area (HDA). A possible role for lobule IX of the posterior vermis in cardiovascular control is discussed in relation to published physiological and neuroanatomical studies and the results gained in the present study.
... Cerebellar lesions or pharmacological inactivation of the cerebellar cortex or deep cerebellar nuclei have been employed to assess the contribution of the cerebellum to fear learning and memory (Supple et al., 1987(Supple et al., , 1988Sacchetti et al., 2002Sacchetti et al., , 2007. In rats, cerebellar vermal lesions mainly targeting lobules IV and V or VIII induced a deficit in innate fear-evoked freezing to a predator (cat) with normal contextual fear memory retrieval, whereas cerebellar hemispheric lesions targeting Crus I and II induced a deficit in contextual fear memory retrieval without affecting the innate fear response to a predator (Supple et al., 1987(Supple et al., , 1988Koutsikou et al., 2014). ...
... Cerebellar lesions or pharmacological inactivation of the cerebellar cortex or deep cerebellar nuclei have been employed to assess the contribution of the cerebellum to fear learning and memory (Supple et al., 1987(Supple et al., , 1988Sacchetti et al., 2002Sacchetti et al., , 2007. In rats, cerebellar vermal lesions mainly targeting lobules IV and V or VIII induced a deficit in innate fear-evoked freezing to a predator (cat) with normal contextual fear memory retrieval, whereas cerebellar hemispheric lesions targeting Crus I and II induced a deficit in contextual fear memory retrieval without affecting the innate fear response to a predator (Supple et al., 1987(Supple et al., , 1988Koutsikou et al., 2014). It is worth noting that only contextual fear memory was assessed without the use of sensory stimuli such as a tone or light as a CS in these studies (Supple et al., 1987(Supple et al., , 1988. ...
... In rats, cerebellar vermal lesions mainly targeting lobules IV and V or VIII induced a deficit in innate fear-evoked freezing to a predator (cat) with normal contextual fear memory retrieval, whereas cerebellar hemispheric lesions targeting Crus I and II induced a deficit in contextual fear memory retrieval without affecting the innate fear response to a predator (Supple et al., 1987(Supple et al., , 1988Koutsikou et al., 2014). It is worth noting that only contextual fear memory was assessed without the use of sensory stimuli such as a tone or light as a CS in these studies (Supple et al., 1987(Supple et al., , 1988. Another study used a pharmacological inactivation approach with tetrodotoxin (TTX), a voltage-gated sodium channel blocker, in the cerebellar vermis or interpositus nuclei (IpN) at different post-training intervals after fear conditioning with multiple tone and foot shock pairings (Sacchetti et al., 2002). ...
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Accumulating evidence indicates that the cerebellum is critically involved in modulating non-motor behaviors, including cognition and emotional processing. Both imaging and lesion studies strongly suggest that the cerebellum is a component of the fear memory network. Given the well-established role of the cerebellum in adaptive prediction of movement and cognition, the cerebellum is likely to be engaged in the prediction of learned threats. The cerebellum is activated by fear learning, and fear learning induces changes at multiple synaptic sites in the cerebellum. Furthermore, recent technological advances have enabled the investigation of causal relationships between intra- and extra-cerebellar circuits and fear-related behaviors such as freezing. Here, we review the literature on the mechanisms underlying the modulation of cerebellar circuits in a mammalian brain by fear conditioning at the cellular and synaptic levels to elucidate the contributions of distinct cerebellar structures to fear learning and memory. This knowledge may facilitate a deeper understanding and development of more effective treatment strategies for fear-related affective disorders including post-traumatic stress or anxiety related disorders.
... In rhesus monkeys, vermal lesions result in docile behaviour and reduced aggression, whereas no such emotional-behavioural consequences were found after lesions to the lateral cerebellum [114]. Freezing behaviour, a defensive mechanism in rats in response to fearful or painful stimuli, diminished in the presence of a cat in rats with vermal lesions [115]. In addition to freezing behaviour, rats are known to exhibit specific behavioural responses in the presence of fear-inducing stimuli, such as thigmotaxis (wall hugging), considered to be an adaptive response in attempts to reduce possible predator attacks [116]. ...
... In addition to freezing behaviour, rats are known to exhibit specific behavioural responses in the presence of fear-inducing stimuli, such as thigmotaxis (wall hugging), considered to be an adaptive response in attempts to reduce possible predator attacks [116]. Vermal-lesioned rats also demonstrate reduced freezing behaviour and thigmotaxis in an open field test [115]. Such comparative data suggest an evolutionarily conserved role for the vermal cerebellum in regulating emotional behaviour. ...
... As in human research, fear-conditioning paradigms have also been used extensively in non-human animals to investigate the cerebellum and emotional processing. Corroborating the significance of the vermis in this context, several studies report impaired acquisition of elements of the conditioned fear response after vermal lesions, including diminished bradycardia in rats [115,117] and rabbits [118]. Of note is the finding that lesioning did not affect baseline heart rate or heart rate in response to the tone alone [117]. ...
Article
Full-text available
The notion that the cerebellum is a central regulator of motor function is undisputed. There exists, however, considerable literature to document a similarly vital role for the cerebellum in the regulation of various non-motor domains, including emotion. Research from numerous avenues of investigation (i.e., neurophysiological, behavioural, electrophysiological, imagining, lesion, and clinical studies) have documented the importance of the cerebellum, in particular, the vermis, in affective processing that appears preserved across species. The cerebellum possesses a distinct laminar arrangement and highly organized neuronal circuitry. Moreover, the cerebellum forms reciprocal connections with several brain regions implicated in diverse functional domains, including motor, sensory, and emotional processing. It has been argued that these unique neuroanatomical features afford the cerebellum with the capacity to integrate information about an organism, its environment, and its place within the environment such that it can respond in an appropriate, coordinated fashion, with such theories extending to the regulation of emotion. This review puts our current understanding of the cerebellum and its role in behaviour in historical perspective, presents an overview of the neuroanatomical and functional organization of the cerebellum, and reviews the literature describing the involvement of the cerebellum in emotional regulation in both humans and non-human animals. In summary, this review discusses the importance of the functional connectivity of the cerebellum with various brain regions in the ability of the cerebellum to effectively regulate emotional behaviour.
... In rhesus monkeys, vermal lesions result in docile behaviour and reduced aggression, whereas no such emotional-behavioural consequences were found after lesions to the lateral cerebellum [114]. Freezing behaviour, a defensive mechanism in rats in response to fearful or painful stimuli, diminished in the presence of a cat in rats with vermal lesions [115]. In addition to freezing behaviour, rats are known to exhibit specific behavioural responses in the presence of fear-inducing stimuli, such as thigmotaxis (wall hugging), considered to be an adaptive response in attempts to reduce possible predator attacks [116]. ...
... In addition to freezing behaviour, rats are known to exhibit specific behavioural responses in the presence of fear-inducing stimuli, such as thigmotaxis (wall hugging), considered to be an adaptive response in attempts to reduce possible predator attacks [116]. Vermal-lesioned rats also demonstrate reduced freezing behaviour and thigmotaxis in an open field test [115]. Such comparative data suggest an evolutionarily conserved role for the vermal cerebellum in regulating emotional behaviour. ...
... As in human research, fear-conditioning paradigms have also been used extensively in non-human animals to investigate the cerebellum and emotional processing. Corroborating the significance of the vermis in this context, several studies report impaired acquisition of elements of the conditioned fear response after vermal lesions, including diminished bradycardia in rats [115,117] and rabbits [118]. Of note is the finding that lesioning did not affect baseline heart rate or heart rate in response to the tone alone [117]. ...
Article
Full-text available
The notion that the cerebellum is a central regulator of motor function is undisputed. There exists, however, considerable literature to document a similarly vital role for the cerebellum in the regulation of various non-motor domains, including emotion. Research from numerous avenues of investigation (i.e., neurophysiological, behavioural, electrophysiological, imagining, lesion, and clinical studies) have documented the importance of the cerebellum, in particular, the vermis, in affective processing that appears preserved across species. The cerebellum possesses a distinct laminar arrangement and highly organized neuronal circuitry. Moreover, the cerebellum forms reciprocal connections with several brain regions implicated in diverse functional domains, including motor, sensory, and emotional processing. It has been argued that these unique neuroanatomical features afford the cerebellum with the capacity to integrate information about an organism, its environment, and its place within the environment such that it can respond in an appropriate, coordinated fashion, with such theories extending to the regulation of emotion. This review puts our current understanding of the cerebellum and its role in behaviour in historical perspective, presents an overview of the neuroanatomical and functional organization of the cerebellum, and reviews the literature describing the involvement of the cerebellum in emotional regulation in both humans and non-human animals. In summary, this review discusses the importance of the functional connectivity of the cerebellum with various brain regions in the ability of the cerebellum to effectively regulate emotional behaviour.
... Some evidence underscores a functional deactivation or disconnection lesion effect (Grill et al., 2004;McIntyre et al., 2004;Kern and Kumar, 2007;Birdno and Grill, 2008;Deniau et al., 2010). This notion appears to be consistent with some behavioural effects seen in classical vermal lesion experiments (Supple et al., 1987;Supple et al., 1988;Bobee et al., 2000;Sacchetti et al., 2002). ...
... Some animals were mounted then subjected to a surgical ablation or disconnection of the CBv [CBv (x)] or parts of the right lateral cerebellum [LCB(x)] 1.5 h before 5-HT recordings. Ablation procedures were modified from previous methods (Supple et al., 1987;Supple et al., 1988;Aoki et al., 2013). For CBv(x), craniotomy was performed by drilling a hole on the skull midline 1 mm from the interaural line, extending 3 cm side to side. ...
... This is in agreement with other studies reporting that decreasing Purkinje cell-imposed inhibition of deep cerebellar nuclei generates enhanced excitatory output from these deep nuclei (Ishikawa et al., 2014). Stimulation of fastigial transmission, or its output fibers (superior cerebellar peduncle) have been shown to engender hypermotionality or adverse behavioural consequences, as already shown by others (Nashold and Slaughter, 1969;Konarski et al., 2005;Krupa et al., 1993;Supple and Kapp, 1993;Hansel et al., 2001;Strata et al., 2011;Albert et al., 1985;Bobee et al., 2000;Berntson and Schumacher, 1980;Supple et al., 1987;Supple et al., 1988;Bobee et al., 2000;Sacchetti et al., 2002;Sacchetti et al., 2009;Bauer et al., 2011). Taken together these results provide evidence that the cerebellar vermis can potentially regulate the activity of DR 5-HT neurons and that CBv-Stim induces strong antidepressant-like effects in preclinical models. ...
Article
Some evidence suggests that the cerebellum modulates affect via connectivities with mood-regulating corticolimbic structures, such as the prefrontal cortex and monoamine nuclei. In rats exposed to chronic unpredictable stress (CUS), we examined the neuro-behavioural effects of high frequency stimulation and surgical ablation/disconnection of the cerebellar vermis. CUS reduced sucrose preference, increased novelty-induced feeding suppression and passive coping. These depressive-like behaviours were associated with decreased cerebellar zif268 expression, indicating possible cerebellar involvement in stress pathology. These were paralleled by decreased vermal Purkinje simple and complex spiking activity and raphe serotonergic activity. Protracted (24-h) vermal stimulation reversed these behavioural deficits through serotonin-mediated mechanisms since this effect was abrogated by the serotonin-depleting agent pCPA. Vermal stimulation and disconnection lesion also enhanced serotonergic activity, but did not modify prefrontocortical pyramidal firing. This effect was likely mediated by 5-HT1A receptors (5-HT1AR). Indeed, acute vermal stimulation mimicked the effect of the 5-HT1AR agonist 8-OH-DPAT in inhibiting serotonergic activity, which was prevented by pre-treatment with the 5-HT1AR antagonist WAY100,635. These results demonstrate vermal involvement in depressive-type behaviour via its modulatory action on serotonergic neurons. They further suggest that vermal and mPFC stimulation may bestow therapeutic benefits via parallel pathways.
... 8,19 Further work should examine putative developmental changes in amygdala-cerebellar iFC, particularly in light of the cerebellum's protracted developmental course that continues through adolescence. 51 Basic research supports anatomical connectivity between the cerebellar vermis and amygdala, [52][53][54] and evidence from human and animal studies indicates a primary role of the cerebellum in fear expression and memory [54][55][56] Thus, together with the altered findings of CMA-subgenual ACC iFC, alterations in amygdala-cerebellar iFC in adolescents with GAD suggest disruptions in normative fear processing, although confirmation of such deficits awaits further study. ...
... 8,19 Further work should examine putative developmental changes in amygdala-cerebellar iFC, particularly in light of the cerebellum's protracted developmental course that continues through adolescence. 51 Basic research supports anatomical connectivity between the cerebellar vermis and amygdala, [52][53][54] and evidence from human and animal studies indicates a primary role of the cerebellum in fear expression and memory [54][55][56] Thus, together with the altered findings of CMA-subgenual ACC iFC, alterations in amygdala-cerebellar iFC in adolescents with GAD suggest disruptions in normative fear processing, although confirmation of such deficits awaits further study. ...
Article
Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala-based circuitry; the present study examines this issue in adolescents with GAD. Resting state fMRI scans were obtained from 15 adolescents with GAD and 20 adolescents without anxiety who were group matched on age, sex, scanner, and intelligence. Functional connectivity of the centromedial, basolateral, and superficial amygdala subdivisions was compared between groups. We also assessed the relationship between amygdala network dysfunction and anxiety severity. Adolescents with GAD exhibited disruptions in amygdala-based intrinsic functional connectivity networks that included regions in medial prefrontal cortex, insula, and cerebellum. Positive correlations between anxiety severity scores and amygdala functional connectivity with insula and superior temporal gyrus were also observed within the GAD group. There was some evidence of greater overlap (less differentiation of connectivity patterns) of the right basolateral and centromedial amygdala networks in the adolescents with, relative to those without, GAD. These findings suggest that adolescents with GAD manifest alterations in amygdala circuits involved in emotion processing, similar to findings in adults. In addition, disruptions were observed in amygdala-based networks involved in fear processing and the coding of interoceptive states.
... From 1958, it was mentioned that vermal stimulation could inhibited some sham rage-related manifestations like mydriasis or struggling and lashing of the tail in decerebrate cats [189]. Furthermore, Supple et al. showed that rats with lesion of the vermis exhibited reduced threatening-elicited freezing [190]. In addition to these unlearned modifications of emotional behaviours, some studies demonstrated the involvement of the cerebellum and more particularly of the vermis in aversive conditioned autonomic responses. ...
... In addition to these unlearned modifications of emotional behaviours, some studies demonstrated the involvement of the cerebellum and more particularly of the vermis in aversive conditioned autonomic responses. For instance, bradycardia conditioning was found to be impaired by vermal lesion both in rabbits [191] and rats [190,192]. Comparable results were also obtained in goldfish [193]. Unchanged baseline heart rates in some cases [188,192] moreover indicated that the cerebellar role in aversive conditioning extended beyond the only execution of motor response and is concerned with the conditioning process itself. ...
Chapter
Although some authors suspected the roles of the cerebellum exceeded the motor sphere from the XIXth century, well documented studies on the topic of non-motor cerebellar functions began to be seriously carried out only from the 70's. Thus, it was suggested that cerebellar patients presenting various types of impairments, whether inherited or traumatic, exhibited some emotional and cognitive disruptions. Conversely, some cerebellar abnormalities were detected in some individuals suffering from mental pathology like autism or schizophrenia. In addition to these clinical data, studies on healthy subjects permitted to show particular patterns of activation in the cerebellum during execution of non-motor task. Despite a growing consensus about the non-motor functions of the cerebellar structures, some passionate controversies about their precise nature (that is what does the cerebellum exactly do) remain. These controversies principally arise from methodological issues encountered in human studies. Animal experimentation represents a precious tool to bypass such issues. So, either the using of cerebellar mutant mice and that of focally lesioned laboratory species permitted to investigate more precisely and systematically the specific role of the cerebellar structures (i.e. the cerebellar cortex and the cerebellar nuclei) in non-motor functions like spatial navigation, learning and regulation of emotions. The aim of the present paper is to extensively review the studies using animal to shed light on the non-motor functions of cerebellar pathways.
... In humans, structural and functional abnormalities can sometimes lead to impaired mood regulation and anxiety disorders (the cerebellar cognitive affect syndrome) [248][249][250][251][252]. In addition, neuroimaging studies have found changes in BOLD signal in the human cerebellum during fear learning paradigms [for review see 253]. In many cases, such changes are associated with the midline cerebellar vermis [249,254,255], and experimental studies in animals have found that lesions and other interventions of this cerebellar compartment have effects on defensive behaviors evoked by emotionally salient events [256][257][258][259][260][261][262][263][264]. ...
... However, large cerebellar lesions involving vermal lobules III-VIII have shown various behavioral changes in relation to fearful or predator-prey interactions in rats. These include (i) fewer signs of fear when animals were placed in a brightly lit arena versus a dimly lit arena; (ii) decreases in freezing behavior and other signs of fear in the presence of a cat; (iii) faster recovery time than controls to the neophobic response to a novel taste test; and (v) attenuated spontaneous predation of mice [261,264]. ...
Article
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The compartmentalization of the cerebellum into modules is often used to discuss its function. What, exactly, can be considered a module, how do they operate, can they be subdivided and do they act individually or in concert are only some of the key questions discussed in this consensus paper. Experts studying cerebellar compartmentalization give their insights on the structure and function of cerebellar modules, with the aim of providing an up-to-date review of the extensive literature on this subject. Starting with an historical perspective indicating that the basis of the modular organization is formed by matching olivocorticonuclear connectivity, this is followed by consideration of anatomical and chemical modular boundaries, revealing a relation between anatomical, chemical, and physiological borders. In addition, the question is asked what the smallest operational unit of the cerebellum might be. Furthermore, it has become clear that chemical diversity of Purkinje cells also results in diversity of information processing between cerebellar modules. An additional important consideration is the relation between modular compartmentalization and the organization of the mossy fiber system, resulting in the concept of modular plasticity. Finally, examination of cerebellar output patterns suggesting cooperation between modules and recent work on modular aspects of emotional behavior are discussed. Despite the general consensus that the cerebellum has a modular organization, many questions remain. The authors hope that this joint review will inspire future cerebellar research so that we are better able to understand how this brain structure makes its vital contribution to behavior in its most general form.
... Using the rs-FC method, a previous study evaluated the rs-FC between the amygdala subregions and anterior regions of the cerebellum in healthy people with no history of psychiatric or neurological illness. 35 Basic research supports anatomical connectivity between the amygdala and cerebellar vermis, 69,70 and the vermis has been implicated in fear responses. [70][71][72] Generalized anxiety disorder (GAD) patients have disruptions in the FC between the amygdala and cerebellum, which may reflect a disruption in fear learning among adolescents with GAD. ...
... 35 Basic research supports anatomical connectivity between the amygdala and cerebellar vermis, 69,70 and the vermis has been implicated in fear responses. [70][71][72] Generalized anxiety disorder (GAD) patients have disruptions in the FC between the amygdala and cerebellum, which may reflect a disruption in fear learning among adolescents with GAD. 73 Strong differential connectivity was also observed between the CM subregion of the amygdala and the cerebellum (especially the vermis) in patients with GAD, which supports the evidence that the cerebellum, in particular the vermis, plays a role in emotional processes through connectivity with the CM subregion of the amygdala. ...
Article
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Background: The amygdala is one of the core areas of the emotional circuits. Previous neuroimaging studies have revealed that patients with obstructive sleep apnea (OSA) have aberrant structure and function in several brain areas (including the amygdala). However, the resting-state functional connectivity (rs-FC) of amgydala subregions remains uncertain. Objective: To determine whether aberrant rs-FC exists between the amygdala subregions and other brain areas and whether such abnormalities are related to emotional disorders and cognitive impairment in OSA. Methods: The resting-state functional magnetic resonance imaging (rs-fMRI) data of 40 male severe OSA patients and 40 matched healthy controls (HCs) were collected. The rs-FC between the amygdala subregions and other brain areas was compared between the two groups. The correlations between aberrant rs-FC and clinical variables and neuropsychological assessments were evaluated. Results: Compared with the HCs, the OSA patients showed significantly increased rs-FC between the left dorsal amygdala (DA) and the anterior lobe of the cerebellum, among the left ventrolateral amygdala (VA), the left inferior frontal gyrus (IFG) and the left superior temporal gyrus (STG), and between the right VA and the left IFG. However, significantly decreased rs-FC was observed between the right DA and the right prefrontal cortex (PFC) in OSA patients. No regional differences in rs-FC were found between the OSA patients and HCs in the bilateral medial amygdala (MA). Conclusion: In this study, male severe OSA patients showed complex rs-FC patterns in the amygdala subregions, which may be the result of OSA-related selective damage to the amygdala, and abnormal rs-FC between the amygdala subregions and brain regions associated with emotional, cognitive and executive functions may partly explain the affective deficits and cognitive impairment observed in male severe OSA patients.
... In humans, structural and functional abnormalities can sometimes lead to impaired mood regulation and anxiety disorders (the cerebellar cognitive affect syndrome) [248][249][250][251][252]. In addition, neuroimaging studies have found changes in BOLD signal in the human cerebellum during fear learning paradigms [for review see 253]. In many cases, such changes are associated with the midline cerebellar vermis [249,254,255], and experimental studies in animals have found that lesions and other interventions of this cerebellar compartment have effects on defensive behaviors evoked by emotionally salient events [256][257][258][259][260][261][262][263][264]. ...
... However, large cerebellar lesions involving vermal lobules III-VIII have shown various behavioral changes in relation to fearful or predator-prey interactions in rats. These include (i) fewer signs of fear when animals were placed in a brightly lit arena versus a dimly lit arena; (ii) decreases in freezing behavior and other signs of fear in the presence of a cat; (iii) faster recovery time than controls to the neophobic response to a novel taste test; and (v) attenuated spontaneous predation of mice [261,264]. ...
Article
Full-text available
In the original version of this paper, the Title should have been written with "A Consensus paper" to read "Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper".
... More recently, several papers addressed the issue of the cerebellar participation to emotional processes. The results have been obtained by means of new cellular technologies, of brain imaging and by studying behaviorally induced changes in the brain (Sacchetti et al. 2005, Strick et al. 2009, Schmahmann et al. 2009). For a more detailed history on cerebellar functions seeGlickstein et al. (2009). ...
... An increasing amount of evidence has confirmed that the cerebellum is indeed involved in emotional behavior and particularly in fear-related processes. Vermal lesions decrease the reactivity of animals to fearful stimuli and attenuate a variety of reactions related to fear such as the freezing response of a rat in the presence of a cat, fear behavior in an open field and neophobic reactions (Snider and Maiti 1976, Bernston and Torello 1982, Supple et al. 1987). Furthermore the cerebellar cognitive affective syndrome, that occurs when lesions involve the vermis and fastigial nucleus, implies, in adult and children, a dysregulation of affect (Schmahmann and Sherman 1998). ...
Article
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In the past decade, a growing body of evidence suggests that in addition to its role in motor control, the cerebellum may be involved in cognitive and emotional functions like fear and anxiety. Moreover cerebellar pathologies have also been correlated with various emotional disorders such as depression and autism. Furthermore the same studies have shown that the integrity of the cerebellar vermis is necessary for the formation of new memory traces related to aversive stimuli. Fear is important because it may trigger a set of defensive reactions aimed at dealing with a threatening environment. For this reason fear responses have been evolutionarily conserved from fish to humans. Fear learning can be assessed using a Pavlovian conditioning paradigm. Here a neutral stimulus serves as conditioned stimulus (CS), and it is repeatedly associated with an aversive one, usually a foot-shock, called unconditioned stimulus (US). As a result of this pairing, the CS comes to elicit a set of spontaneous defensive responses that include freezing, increased heart rate, and startling. manipulation of the vermis affects these responses, and its reversible inactivation during the consolidation phase impairs fear memory. The neural correlate of cerebellar involvement in fear consolidation is provided by a behaviorally induced long-term increase of synaptic efficacy between parallel fibers and a Purkinje cell in the cerebellar cortex. This increase is specific of this synapse and it is not present in the climbing fiber synapse. In addition, in hotfoot mice, with a primary deficiency of parallel fiber to Purkinje cell synapse, short- and long-term fear memories are affected. Similar synaptic changes after fear conditioning are well documented in the amygdala and hippocampus, providing a link between emotional experiences and changes in neural activity. All these data support the idea that the cerebellum participates in fear learning. The functional interconnection of the vermis with hypothalamus, amygdala, and hippocampus suggests a more complex role of the cerebellum as part of an integrated network regulating emotional behavior.
... Several studies have shown that the cerebellum has functional connections with fear-related areas, including the PAG, the amygdala, and the PFC [22][23][24][25][26] . In accordance with the existence of such connections, Pavlovian fear conditioning affects cerebellar plasticity 27 , post-conditioning cerebellar inactivation affects memory consolidation 28 , and cerebellar lesions-or inactivation-modulate freezing 24,29 . ...
Article
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Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. Moreover, FN-vlPAG projections also modulate extinction learning. We also found a FN-parafascicular thalamus pathway, which may relay cerebellar influence to the amygdala and modulates anxiety behaviors. Overall, our results reveal multiple contributions of the cerebellum to the emotional system.
... DCN neurons in the FN make synapses onto diverse types of neurons in the vlPAG, because studies have demonstrated anatomical and functional synaptic connections onto glutamatergic, GABAergic, and dopaminergic neurons of the vlPAG (Frontera et al., 2020;Vaaga et al., 2020). Considering the possible involvement of the cerebellum in freezing behaviors (Supple et al., 1987(Supple et al., , 1988Sacchetti et al., 2002Sacchetti et al., , 2004Koutsikou et al., 2014), the identification of network connections would lead to the idea that the cerebellar regulation of vlPAG plays a role in freezing behaviors. One study supported this idea by showing that cerebellar inputs from the FN modulate dopamine interneurons in the vlPAG and in turn regulate the activity of Chx10-expressing glutamatergic neurons in the vlPAG, which reliably triggered freezing upon activation (Vaaga et al., 2020). ...
Article
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The cerebellum has a long history in terms of research on its network structures and motor functions, yet our understanding of them has further advanced in recent years owing to technical developments, such as viral tracers, optogenetic and chemogenetic manipulation, and single cell gene expression analyses. Specifically, it is now widely accepted that the cerebellum is also involved in non-motor functions, such as cognitive and psychological functions, mainly from studies that have clarified neuronal pathways from the cerebellum to other brain regions that are relevant to these functions. The techniques to manipulate specific neuronal pathways were effectively utilized to demonstrate the involvement of the cerebellum and its pathways in specific brain functions, without altering motor activity. In particular, the cerebellar efferent pathways that have recently gained attention are not only monosynaptic connections to other brain regions, including the periaqueductal gray and ventral tegmental area, but also polysynaptic connections to other brain regions, including the non-primary motor cortex and hippocampus. Besides these efferent pathways associated with non-motor functions, recent studies using sophisticated experimental techniques further characterized the historically studied efferent pathways that are primarily associated with motor functions. Nevertheless, to our knowledge, there are no articles that comprehensively describe various cerebellar efferent pathways, although there are many interesting review articles focusing on specific functions or pathways. Here, we summarize the recent findings on neuronal networks projecting from the cerebellum to several brain regions. We also introduce various techniques that have enabled us to advance our understanding of the cerebellar efferent pathways, and further discuss possible directions for future research regarding these efferent pathways and their functions.
... Most of these studies, however, have focused on the lateral cerebellar cortex and its projections to the interpositus nucleus. Moreover, previous studies in rats had indicated a role for the cerebellar vermis in unconditioned fear reactions but found little evidence of the vermis in conditioned fear (Supple et al., 1987Supple et al., , 1988). However, recent work suggests the vermis may have a role in conditioned freezing in rats (Sacchetti et al., 2002Sacchetti et al., , 2005). ...
Chapter
The capacity to learn and retain information, whether it is the sequence and rhythm of muscle movements required for a motor skill or the details of a traumatic emotional experience, imbues organisms with an enor- mous advantage for coping with an ever-changing world. How the brain forges memory from experience has been a question of considerable interest to psychologists and neuroscientists for decades. What has become clear in the last several decades is that memory representations are not monolithic and are therefore not wrought by a singular core of specialized brain tissue. Rather, multiple brain systems and regions participate in the encoding and storage of many different types of memories for skills, emotions, facts, and episodes, and so on.
... The cerebellum, specifically the vermis, plays a role in fear and avoidant behaviors. For example, lesioning the vermis alters fear responses by decreasing freezing and increasing open field exploration [110]. On other other hand, stimulating the vermis induces fear responses, such as increased amplitude of the acoustic startle response [111], indicating cerebellar modulation of species-specific behaviors beyond coordination of muscle movements. ...
... For example, group differences observed in amygdala circuits implicated in fear learning and regulation were similar to those observed between individuals with and without anxiety disorders. These circuits consist of the amygdala-subgenual ACC, particularly associated with fear extinction and expression (Etkin, Egner, & Kalisch, 2011;Milad et al., 2007;Quirk, Likhtik, Pelletier, & Pare, 2003) and the amygdala-cerebellum, particularly associated with fear learning and memory (Sacchetti, Sacco, & Strata, 2007;Sacchetti, Scelfo, & Strata, 2005;Supple, Leaton, & Fanselow, 1987). This is further supported by a recent study suggesting that behaviorally inhibited adults exhibit facilitated fear learning even in the absence of an anxiety disorder (Myers et al., 2012). ...
... Consistent with this, deficits in cerebellar function are associated with impaired emotional attention and perception, as seen in depression, anxiety, schizophrenia, and post-traumatic stress disorder (Yin et al., 2011;Roy et al., 2013;Parker et al., 2014;Phillips et al., 2015), as well as cognitive and emotional disturbances collectively known as cerebellar cognitive affective syndrome (Schmahmann and Sherman, 1998). Animal models have recapitulated some of these findings, with selective mutations, damage or inactivation of the rodent cerebellum resulting in altered acquisition or extinction of learned defensive responses, and impaired social and goal-directed behavior, without motor deficits (Supple et al., 1987;Supple and Leaton, 1990;Sebastiani et al., 1992;Bauer et al., 2011;Lorivel et al., 2014;Otsuka et al., 2016;Xiao et al., 2018;Carta et al., 2019;Frontera et al., 2020;Han et al., 2021;Baek et al., 2022;Lawrenson et al., 2022). ...
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The cerebellum is emerging as a powerful regulator of cognitive and affective processing and memory in both humans and animals and has been implicated in affective disorders. How the cerebellum supports affective function remains poorly understood. The short-latency (just a few milliseconds) functional connections that were identified between the cerebellum and amygdala—a structure crucial for the processing of emotion and valence—more than four decades ago raise the exciting, yet untested, possibility that a cerebellum-amygdala pathway communicates information important for emotion. The major hurdle in rigorously testing this possibility is the lack of knowledge about the anatomy and functional connectivity of this pathway. Our initial anatomical tracing studies in mice excluded the existence of a direct monosynaptic connection between the cerebellum and amygdala. Using transneuronal tracing techniques, we have identified a novel disynaptic circuit between the cerebellar output nuclei and the basolateral amygdala. This circuit recruits the understudied intralaminar thalamus as a node. Using ex vivo optophysiology and super-resolution microscopy, we provide the first evidence for the functionality of the pathway, thus offering a missing mechanistic link between the cerebellum and amygdala. This discovery provides a connectivity blueprint between the cerebellum and a key structure of the limbic system. As such, it is the requisite first step toward obtaining new knowledge about cerebellar function in emotion, thus fundamentally advancing understanding of the neurobiology of emotion, which is perturbed in mental and autism spectrum disorders.
... Courchesne et al. hypothesized that damage to the cerebellum, may be important in causing the autistic syndrome. This assertion is strengthened by the fact that the cerebellar vermis has extensive direct and indirect connections with brain-stem and limbic regions that have been implicated in the control of complex behaviors and affects (Berntson & Torello, 1982;Supple, Leaton, & Fanselow, 1987). ...
Chapter
Developmental disorders affecting intelligence and behavior are among the most mystifying diseases of humankind. This is because they are primarily caused by abnormalities in the development of the most complex human organ, the brain. Perhaps the reason so little is understood about mental retardation, autism, childhood schizophrenia, attention deficit disorder, specific learning disorders, and Tourette disorder is that very little is still understood about how a normal brain develops. The premise of this chapter is that the key to understand these illnesses is an understanding of the processes involved in neurodevelopment.
... Until recently, the cerebellum was generally considered not to be a part of this network. However, there is good evidence in cats and rodents that vermal regions of the cerebellum contribute to motor and autonomic components of defensive states: inactivation of vermal cerebellar cortex (lobules IV-VIII), or one of its main output nuclei (medial cerebellar nucleus [MCN], aka fastigial nucleus), leads to deficits in fear-related behaviours such as context-conditioned bradycardia (Supple and Leaton, 1990) the expression of innate fear (Supple et al., 1987;Koutsikou et al., 2014); and fear-conditioned freezing behaviour (Asdourian and Frerichs, 1970;Sacchetti et al., 2002;Sacchetti et al., 2005;Koutsikou et al., 2014). In addition, the emission of USVs has been related to cerebellar function (Fujita et al., 2008;Fujita-Jimbo and Momoi, 2014;Toledo et al., 2019), and inactivation of the cerebellar vermis during innate and conditioned fear unmasks risk assessment rearing behaviour (Koutsikou et al., 2014). ...
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The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in male rat ventrolateral PAG (vlPAG) that encode fear memory through signalling the onset and offset of an auditory-conditioned stimulus during presentation of the unreinforced conditioned tone (CS+) during retrieval. Some units only display CS+ onset or offset responses, and the two signals differ in extinction sensitivity, suggesting that they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to (a) disruption of the temporal precision of vlPAG offset, but not onset responses to CS+, and (b) an increase in duration of freezing behaviour. And (ii) chemogenetic manipulation of the MCN-vlPAG projection during fear acquisition (a) reduces the occurrence of fear-related ultrasonic vocalisations, and (b) during subsequent retrieval, slows the extinction rate of fear-related freezing. These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities.
... The cerebellum is linked with the cerebrum, brainstem, and spinal cord through efferent and afferent fibers, and the cerebellar vermis is connected to the amygdala anatomically in animals (De Bellis et al., 2002). Recently, more and more studies have reported the cerebellum is functionally related to expressing fear and processing fear memory (Supple et al., 1987;Sacchetti et al., 2005). Cerebellar cognitive affective syndrome was observed in patients with cerebellar damage (Stoodley, 2012). ...
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The amygdala and the dorsolateral prefrontal cortex (DLPFC) play important roles in “emotion dysregulation,” which has a profound impact on etiologic research of generalized anxiety disorder (GAD). The present study analyzed both eyes-open and eyes-closed resting state functional MRI (rs-fMRI) of 43 subjects (21 GAD patients with medicine free and 22 matched healthy controls). The amygdala and the DLPFC were defined as regions of interest (ROI) to analyze functional connectivity (FC) in GAD patients compared with healthy controls. The main findings revealed GAD patients had increased FC between the amygdala and the temporal pole compared to healthy controls, which was found in both eyes-open and eyes-closed rs-fMRI. And altered FC between the ROIs and brain regions that mainly belonged to the default mode network (DMN) were found. These findings suggest that the abnormal FC between the amygdala and the temporal pole may contribute to the pathophysiology of GAD, and provide insights into the current understanding of the emotion dysregulation of anxiety disorders.
... Moreover, in non-human animals, the vermis plays an important role in defensive freezing behaviour (Snow, et al., 2014). Vermal-lesioned rats and mice with cerebellar mutations demonstrate reduced freezing and impaired conditioned fear responses, notably diminished bradycardia, a typical physiological index of freezing (Sacchetti et al., 2004;Supple and Leaton, 1990;Supple et al., 1987). Conversely, electrical stimulation of the vermis elicits freezing (Berntson and Torello, 1982). ...
... Most of these studies, however, have focused on the lateral cerebellar cortex and its projections to the interpositus nucleus. Moreover, previous studies in rats had indicated a role for the cerebellar vermis in unconditioned fear reactions, but found little evidence of the vermis in conditioned fear (Supple et al., 1988(Supple et al., , 1987. However, later work suggested the vermis may have a role in conditioned freezing in rats (Sacchetti et al., 2002(Sacchetti et al., , 2005. ...
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... Early reports also showed that lesions of the cerebellar vermis (probably corresponding to the A module) reduced freezing behaviour in rats in response to the presence of cat odour [7]. Similarly, and more recently, localised lesions confined to the lateral vermal lobule VIII, corresponding to the A2 module, cause a reduction in freezing behaviour during both innate and conditioned fear tasks [8]. ...
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Objective The role of the cerebellum in tremor genesis is poorly understood. We measured the quantitative parameters of tremor caused by cerebellar/brainstem lesions to determine the relationship between the localisation of the lesion and the tremor characteristics. Methods We recorded the hand tremor of 77 patients using biaxial accelerometry in resting, postural and intentional position. Center frequency, frequency dispersion, proportional power of 0.9–3 Hz range and intensity were determined. Lesions on MRI/CT scans in inferior olive, cerebellar peduncles, dentate nuclei, cerebellar cortex, red nuclei, substantia nigra were investigated. Results Only 30% of patients with cerebellar/brainstem lesions had pathologic tremor. Tremor was present in postural and intentional position and was characterized by narrow frequency dispersion, a center frequency of 2.4 Hz, and normal intensity. Medulla oblongata lesions caused low intensity tremor, whereas mesencephalon lesions enhanced tremor intensity. In most cases tremor recovered within 4–6 weeks. Discussion Cerebellar/brainstem lesions cause pathologic tremor in 1/3 of the cases. Due to its low intensity and low frequency quantitative measurement is necessary to detect this kind of tremor. Tremor induced by acute lesions in the cerebellum/brainstem tends to recover. Conclusions Tremor evoked by structural lesion of the cerebellum/brainstem is related to a widespread network dysfunction rather than a deficit of a well characterised tremor generator. Significance Our study is the first which provides systematic study on the quantitative parameters of tremor caused by cerebellar/brainstem lesion, and on the relationship between tremor characteristics and the localisation of the lesion.
... Several papers have been devoted to supporting the hypothesis that the cerebellum participates in non-motor functions and that they are involved in emotional processes [27,28,10]. Following vermal lesion in animal experiments, there is a decrease in the reactivity of animals to fear stimuli like when a rodent is facing a cat or in an open field [29][30][31]. In addition, the lesion to the anterior cerebellar vermis severely attenuated the acquisition of conditioned bradycardia [32]. ...
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Great attention has been given so far to cerebellar control of posture and of skilled movements despite the well-demonstrated interconnections between the cerebellum and the autonomic nervous system. Here is a review of the link between these two structures and a report on the recently ac-quired evidence for its involvement in the world of emotions. In rodents, the reversible inactivation of the vermis during the consolidation or the reconsolidation period hampers the reten-tion of the fear memory trace. In this region, there is a long-term potentiation of both the excitatory synapses between the parallel fibres and the Purkinje cells and of the feed-forward inhibition mediated by molecular layer interneurons. This concomitant potentiation ensures the temporal fidelity of the system. Additional contacts between mossy fibre terminals and Golgi cells provide morphological evidence of the poten-tiation of another feed-forward inhibition in the granular layer. Imaging experiments show that also in humans the cerebellum is activated during mental recall of emotional personal epi-sodes and during learning of a conditioned or unconditioned association involving emotions. The vermis participates in fear learning and memory mechanisms related to the expres-sion of autonomic and motor responses of emotions. In humans, the cerebellar hemispheres are also involved at a higher emotional level. The importance of these findings is evident when considering the cerebellar malfunctioning in psychiatric diseases like autism and schizophrenia which are characterized behaviourally by emotion processing impairments. http://link.springer.com/article/10.1007%2Fs12311-015-0649-9
... Further support for non-motor CB roles stems from clinical translational studies, which have linked CB dysfunction with neurodevelopmental disorders, posttraumatic stress disorder, generalized anxiety disorder, addiction, and cognitive and emotional disturbances known as cerebellar cognitive affective syndrome 8,[10][11][12][13][14][15][16][17][18] . These findings are further corroborated by evidence from animal studies, which solidify a role for the CB in the processing of valence, reward, reward anticipation and omission [19][20][21][22][23] ; emotional learning and aggression [24][25][26][27][28][29][30] ; and motivation [31][32][33] . ...
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Traditionally viewed as a motor control center, the cerebellum (CB) is now recognized as an integral part of a broad, long-range brain network that serves limbic functions and motivates behavior. This diverse CB functionality has been at least partly attributed to the multiplicity of its outputs. However, relatively little attention has been paid to CB connectivity with subcortical limbic structures, and nothing is known about how the CB connects to the nucleus accumbens (NAc), a complex striatal region with which the CB shares functionality in motivated behaviors. Here, we report findings from in vivo electrophysiological experiments that investigated the functional connectivity between CB and NAc. We found that electrical microstimulation of deep cerebellar nuclei (DCN) modulates NAc spiking activity. This modulation differed in terms of directionality (excitatory vs. inhibitory) and temporal characteristics, in a manner that depends on NAc subregions: in the medial shell of NAc (NAcMed), slow inhibitory responses prevailed over excitatory ones, whereas the proportion of fast excitatory responses was greater in the NAc core (NAcCore) compared to NAcMed. Slow inhibitory modulation of NAcCore was also observed but it required stronger CB inputs compared to NAcMed. Finally, we observed shorter onset latencies for excitatory responses in NAcCore than in NAcMed, which argues for differential connectivity. If different pathways provide signal to each subregion, the divergence likely occurs downstream of the CB because we did not find any response-type clustering within DCN. Because there are no direct monosynaptic connections between CB and NAc, we performed viral tracing experiments to chart disynaptic pathways that could potentially mediate the newly discovered CB-NAc communication. We identified two anatomical pathways that recruit the ventral tegmental area and intralaminar thalamus as nodes. These pathways and the functional connectivity they support could underlie CB's role in motivated behaviors.
... Early reports also showed that lesions of the cerebellar vermis (probably corresponding to the A module) reduced freezing behaviour in rats in response to the presence of cat odour [7]. Similarly, and more recently, localised lesions confined to the lateral vermal lobule VIII, corresponding to the A2 module, cause a reduction in freezing behaviour during both innate and conditioned fear tasks [8]. ...
Article
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The cerebellum has a striking homogeneous cytoarchitecture and participates in both motor and non-motor domains. Indeed, a wealth of evidence from neuroanatomical, electrophysiological, neuroimaging and clinical studies has substantially modified our traditional view on the cerebellum as a sole calibrator of sensorimotor functions. Despite the major advances of the last four decades of cerebellar research, outstanding questions remain regarding the mechanisms and functions of the cerebellar circuitry. We discuss major clues from both experimental and clinical studies, with a focus on rodent models in fear behaviour, on the role of the cerebellum in motor control, on cerebellar contributions to timing and our appraisal of the pathogenesis of cerebellar tremor. The cerebellum occupies a central position to optimize behaviour, motor control, timing procedures and to prevent body oscillations. More than ever, the cerebellum is now considered as a major actor on the scene of disorders affecting the CNS, extending from motor disorders to cognitive and affective disorders. However, the respective roles of the mossy fibres, the climbing fibres, cerebellar cortex and cerebellar nuclei remains unknown or partially known at best in most cases. Research is now moving towards a better definition of the roles of cerebellar modules and microzones. This will impact on the management of cerebellar disorders.
... The role of the cerebellum could not be related to the execution of an active response, as cerebellectomy impaired performance in a passive avoidance task as well (Guillaumin et al., 1991). Some other early studies showed medial cerebellar lesions decreased fear responses when rats were presented with a predator (Supple et al., 1987), an effect also seen in a lever pressing paradigm (Steinmetz et al., 1993). ...
... Nevertheless, only few studies have directly investigated cerebellar contributions to fear behavior. Thus, Pavlovian fear conditioning affects cerebellar plasticity (Sacchetti et al. 2004), and cerebellar lesions or inactivation modulate freezing response (Supple et al. 1987;Koutsikou et al. 2014). Activation observed in the present study in Crus 2 lobule, as also reported in a previous study (Litaudon et al. 2017), is in accordance with previous data showing that Crus 2 is activated by whisker stimulation (Sharp et al. 1989;Bosman et al. 2010) and by stimulation of the skin of the snout (Armstrong and Drew 1980), both being associated with sniffing. ...
Article
Memory consolidation involves reorganization at both the synaptic and system levels. The latter involves gradual reorganization of the brain regions that support memory and has been mostly highlighted using hippocampal-dependent tasks. The standard memory consolidation model posits that the hippocampus becomes gradually less important over time in favor of neocortical regions. In contrast, this reorganization of circuits in amygdala-dependent tasks has been less investigated. Moreover, this question has been addressed using primarily lesion or cellular imaging approaches thus precluding the comparison of recent and remote memory networks in the same animals. To overcome this limitation, we used microPET imaging to characterize, in the same animals, the networks activated during the recall of a recent versus remote memory in an olfactory cued fear conditioning paradigm. The data highlighted the drastic difference between the extents of the two networks. Indeed, although the recall of a recent odor fear memory activates a large network of structures spanning from the prefrontal cortex to the cerebellum, significant activations during remote memory retrieval are limited to the piriform cortex. These results strongly support the view that amygdala-dependent memories also undergo system-level reorganization, and that sensory cortical areas might participate in the long-term storage of emotional memories.
... Some magnetic resonance imaging (MRI) studies (Dean and McCarthy, 2009) in the humans showed that cerebellum is larger in adult men than women, even when controlling for height. Earlier report by Supple et al. (1987) showed that children and adolescents MRI reveals an 8% differences in cerebellar volume, with cerebellum of males being larger even when controlling for height and weight. Examination of fixed human tissues, using the same MRI by and Malhotra et al. (1959), failed to show volumetric differences in the cerebella of men and women. ...
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Introduction: Sexual dimorphisms in biological structures such as brain and behaviour have been widely recognized in animals and humans. The purpose of this study was to examine whether there are sex differences in the size of the cerebellum with other body traits, such as the head, tail and brain. Methods: Twelve grasscutters comprising of 6 males and 6 females were used in this study. Each brain was extracted from the skull by standard procedures and the mean values of the weights, dimensions and volumes of the brain, cerebellum, head and tail were compared in male and female using quantitative analytical statistical method. Results: The results showed that the absolute mean brain weight and volume obtained in the male was slightly higher than that of the female, while the cerebellar mean weight was slightly higher in the female; although these values were not statistically significant (P> 0.05). The mean cerebellar lengths and widths did not differ between the two sexes (> 0.05), but the mean cerebellar circumference in the male was statistically higher than in the female (P< 0.05). The female cerebellar length was positively correlated with the length of the brain, head, body and tail. Discussion: In conclusion, the brain weight was slightly higher in the male than female, while the cerebellar weight was higher in the female than male. The significantly higher value of the cerebellar circumference in the male may partly be responsible for the big round head seen in the live male grasscutter.
... In animals, the cerebellar verm is connected with the amygdala anatomically [44]. In recent years, a growing number of studies have suggested that the cerebellum is functionally related to expressing fears and processing fear memory [45,46]. The cerebellum performs functions in language processing, cognitive processing, and emotional control [47,48]. ...
Article
Background We aimed to investigate the disruptions of functional connectivity of amygdala-based networks in adolescents with untreated generalized anxiety disorder (GAD). Material/Methods A total of 26 adolescents with first-episode GAD and 20 normal age-matched volunteers underwent resting-state and T1 functional magnetic resonance imaging (fMRI). We analyzed the correlation of fMRI signal fluctuation between the amygdala and other brain regions. The variation of amygdala-based functional connectivity and its correlation with anxiety severity were investigated. Results Decreased functional connectivity was found between the left amygdala and left dorsolateral prefrontal cortex. An increased right amygdala functional connectivity with right posterior and anterior lobes of the cerebellum, insula, superior temporal gyrus, putamen, and right amygdala were found in our study. Negative correlations between GAD scores and functional connectivity of the right amygdala with the cerebellum were also observed in the GAD adolescents. Conclusions Adolescents with GAD have abnormalities in brain regions associated with the emotional processing pathways.
... In support of these functional and anatomical distinctions, older animal studies demonstrated that direct cortical stimulation of the cerebellar vermis and/or the fastigial nucleus (the deep cerebellar nucleus to which the vermis projects) caused "sham rage," while ablation led to indifference and passivity (e.g. rats demonstrated reduced defensive "freezing" in the presence of cats) (Berntson & Schumacher, 1980;Heath, Dempesy, Fontana, & Myers, 1978;Supple, Leaton, & Fanselow, 1987). These studies were among the first to provided evidence that the vermis and fastigial nucleus play a modulatory role in the behavioral and physiological manifestations of emotional behavior. ...
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Background: The Dandy–Walker Malformation (DWM) is a congenital birth malformation that is characterized by a triad of features: cerebellar dysgenesis, cystic dilation of the fourth ventricle, and an enlarged posterior fossa that displaces the dural sinuses and the tentorium. Despite this defining triad, clinical presentation can be highly heterogeneous in part due to severity of structural changes. To date, there been limited consideration of cognitive-behavioral symptoms of DWM in relation to nonmotor functions of the cerebellum, specifically cerebellar cognitive affective syndrome (CCAS). Method: In this case study, we describe the neuropsychological and behavioral profile of a 48-year-old man with DWM who was seen due to concerns, expressed solely by the patient’s father, about his son’s atypical housing, employment and social skills. Results: Neuropsychological test findings revealed high average intellect on standard intellectual measures (WAIS-IV), with stronger verbal (superior) than perceptual reasoning (average) skills. Across all cognitive domains, performance was generally within expectations, although bilateral fine motor skills were impaired. In contrast, he exhibited weaknesses on nontraditional neuropsychological measures assessing orbitofrontal-limbic circuitry, including reward sensitivity decision making and indices of threat-related emotional physiology. Conclusions: Through the use of traditional and nontraditional neuropsychological measures, subtle cognitive weaknesses in fronto-executive and affective regulation were illuminated and likely explain the patient’s functional difficulties. Etiologically, these findings are consistent with the nonmotor functions of the cerebellum as described by CCAS.
... Uno dei protocolli piu Á diffusi per lo studio della reazione di paura nel roditore consiste nel misurare la durata dello stato di immobilita Á dell'animale dopo somministrazione di uno stimolo che costituisce minaccia o pericolo. La lesione del verme diminuisce la risposta di immobilita Á dell'animale di fronte ad un gatto oppure ad un ambiente aperto (Snider e Maiti, 1976;Berntson e Torello, 1982;Supple et al., 1987). Al contrario, la stimolazione elettrica del verme potenzia le risposte di paura (Berntson e Torello, 1982;Snider e Maiti, 1976). ...
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Recenti ricerche hanno dimostrato che il cervelletto è coinvolto nel controllo delle funzioni cognitive e nelle emozioni come paura ed ansia. Inoltre, alcune sue patologie sono spesso associate a disturbi dell'umore, come depressione ed autismo. Oltre a ciò, da questi studi è emerso che l'integrità del verme dorsale è necessaria per la formazione di nuove tracce mnemoniche legate a stimoli avversivi. Infatti, il blocco reversibile dell'attività di questa area cerebrale riduce la formazione di nuove tracce mnemoniche legate alla paura. Particolarmente importante in questo processo è la sinapsi tra fibra parallela e cellula di Purkinje. Infatti, in topi mutanti con alterata funzione di questa sinapsi, si ha una riduzione significativa delle capacità di memorizzazione di eventi potenzialmente pericolosi. Il meccanismo cellulare alla base di questi processi è un potenziamento a lungo termine della sinapsi tra fibra parallela e cellula di Purkinje, ottenuto tramite una modificazione dei recettori per il glutammato della cellula di Purkinje., Precedentemente, una forma analoga di plasticità era stata trovata nell'amigdala e nell'ippocampo in seguito ai processi di apprendimento legati a stimoli di pericolo, ed è stata interpretata come il meccanismo cellulare attraverso cui queste sedi formano nuove tracce mnemoniche. Dall'insieme di questi studi emerge pertanto che il cervelletto fa parte di un complesso circuito neurale, che è in grado di regolare gli stati emotivi e di formare nuovi ricordi legati alle emozioni.
... Exposure of rodents to natural predator odors causes innate fear (Takahashi et al., 2005;Staples, 2010) 80 and the cerebellum is involved in the processing of the fear response to predators as lesions of the 81 cerebellar vermis reduce a freezing response in rats exposed to a cat (Supple et al., 1987). There are 82 extensive connections between the cerebellum and brain regions that are important for defense 83 responses, including the limbic, prefrontal cortex and sympathetic nervous systems (Bostan et al., 2013 suggests a mechanism for controlling the length of Bergmann glial processes. ...
Article
Stress alters brain function by modifying the structure and function of neurons and astrocytes. The fine processes of astrocytes are critical for the clearance of neurotransmitters during synaptic transmission. Thus, experience-dependent remodeling of glial processes is anticipated to alter the output of neural circuits. However, the molecular mechanism(s) that underlie glial structural plasticity are not known. Here we show that a single exposure of male and female mice to an acute stress produced a long-lasting retraction of the lateral processes of cerebellar Bergmann glial cells. These cells express the GluA1 subunit of AMPA-type glutamate receptors and GluA1 knockdown is known to shorten the length of glial processes. We found that stress reduced the level of GluA1 protein and AMPA receptor-mediated currents in Bergmann glial cells and these effects were absent in mice devoid of CPEB3, a protein that binds to GluA1 mRNA and regulates GluA1 protein synthesis. Administration of a β-adrenergic receptor blocker attenuated the reduction in GluA1 and deletion of adenylate cyclase 5 prevented GluA1 suppression. Therefore, stress suppresses GluA1 protein synthesis via an adrenergic/adenylyl cyclase/CPEB3 pathway, and reduces the length of astrocyte lateral processes. Our results identify a novel mechanism for GluA1 subunit plasticity in non-neuronal cells, and suggest a previously unappreciated role for AMPA receptors in stress-induced astrocytic remodeling.Significance statement Astrocytes play important roles in synaptic transmission by extending fine processes around synapses. In this study, we showed that a single exposure to an acute stress triggered a retraction of lateral/fine processes in mouse cerebellar astrocytes. These astrocytes express GluA1, a glutamate receptor subunit known to lengthen astrocyte processes. We showed that astrocytic structural changes are associated with a reduction of GluA1 protein levels. This requires activation of β-adrenergic receptors and is triggered by noradrenaline released during stress. We identified adenylyl cyclase 5 as a downstream effector, an enzyme that elevates cAMP levels, and found that lowering GluA1 levels depends on CPEB3 proteins that bind to GluA1 mRNA. Therefore, stress regulates GluA1 protein synthesis via an adrenergic/adenylyl cyclase/CPEB3 pathway in astrocytes and remodels their fine processes.
... In the limbic cerebellum, the vermis has been associated with basic emotions such as fear, while regions of the posterior cerebellar hemispheres have been associated with complex emotions and social interactions, reflecting the former's anatomical connections with brainstem nuclei controlling autonomic functions and the latter's connections with associative prefrontal cortex controlling theory of mind and higher cognitive functions (Stoodley and Schmahmann, 2009;Watson et al., 2013;Van Overwalle et al., 2014;Strata, 2015;Leggio and Olivito, 2018). Rodent studies have demonstrated that the limbic cerebellum and its connections with the amygdala contribute to fear-related learning (Supple Jr. et al., 1987;Sacchetti et al., 2002;Zhu et al., 2011;Strata, 2015), while human studies (described below) have indicated activity in the vermis in response to both negative and positive emotions (Baumann and Mattingley, 2012;Schraa-Tam et al., 2012). ...
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The basal ganglia and the cerebellum historically have been relegated to a functional role in producing or modulating motor output. Recent research, however, has emphasized the importance of these subcortical structures in multiple functional domains, including affective processes such as emotion recognition, subjective feeling elicitation, and reward valuation. Pathways through the thalamus that connect the basal ganglia and cerebellum directly to each other and with extensive regions of cortex provide a structural basis for their combined influence on limbic function. By regulating cortical oscillations to guide learning and strengthening rewarded behavior or thought patterns to achieve a desired goal state, these regions can shape the way an individual processes emotional stimuli. This review will discuss the basic structure and function of the basal ganglia and cerebellum and propose an updated view of their functional role in human affective processing.
Article
MEDIAVILLA, C., F. MOLINA F. AND A. PUERTO. Bilateral lesions in the cerebellar interpositus-dentate region impair taste aversion learning in rats. PHYSIOL BEHAV 65(1) 25–33, 1998.—Taste Aversion Learning (TAL) has been induced through two different behavioral procedures: a short-term o concurrent (two-daily flavors) and a long-term (one-daily flavor) procedure. For the first, two gustatory/olfactory stimuli are presented separately but at the same time on a daily basis. One of the flavors is paired with simultaneous intragastric administration of hypertonic NaCl and the other is paired with physiological saline. In the long-term procedure, the two stimuli are presented on alternate days, one of them followed by intragastric injection of the aversive stimulus, and the other by saline. The subjects for both types of tests were animals that had been lesioned in the interpositus-dentate region of the cerebellum. The experiments show that the lesions disrupt short-term TAL, but have no effect on long-term TAL. The results are discussed in terms of the role of the cerebellum in relation to TAL and the different anatomical substrates of both learning modalities.
Article
The amygdala and the cerebellum serve two distinctively different functions. The amygdala plays a role in the expression of emotional information, whereas the cerebellum is involved in the timing of discrete motor responses. Interaction between these two systems is the basis of the two-stage theory of learning, according to which an encounter with a challenging event triggers fast classical conditioning of fear-conditioned responses in the amygdala and slow conditioning of motor-conditioned responses in the cerebellum. A third stage was hypothesised when an apparent interaction between amygdala and cerebellar associative plasticity was observed: an adaptive rate of cerebellum-dependent motor-conditioned responses was associated with a decrease in amygdala-dependent fear-conditioned responses, and was interpreted as extinction of amygdala-related fear-conditioned responses by the cerebellar output. To explore this hypothesis, we mimicked some components of classical eyeblink conditioning in anesthetised rats by applying an aversive periorbital pulse as an unconditioned stimulus and a train of pulses to the cerebellar output nuclei as a cerebellar neuronal-conditioned response. The central amygdala multiple unit response to the periorbital pulse was measured with or without a preceding train to the cerebellar output nuclei. The results showed that activation of the cerebellar output nuclei prior to periorbital stimulation produced diverse patterns of inhibition of the amygdala response to the periorbital aversive stimulus, depending upon the nucleus stimulated, the laterality of the nucleus stimulated, and the stimulus interval used. These results provide a putative extinction mechanism of learned fear behavior, and could have implications for the treatment of pathologies involving abnormal fear responses by using motor training as therapy.
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Fragile X syndrome, the leading known cause of heritable mental retardation, is associated with mutations of the FMR1 gene on the X chromosome. Neurobiological research has characterized several gene-brain-function correlations in fragile X syndrome, although no complete pathogenic mechanisms have yet been elucidated. This report summarizes current knowledge of the neurobiology of fragile X syndrome. Published research findings are presented along with a discussion of the relevance of neurobiological data to the neurobehavioral phenotype and genetic mechanisms associated with the FMR1 mutation. © 1995 Wiley-Liss, Inc.
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This book collects the contributions of a number of clinical psychiatrists all over the world, interested in developing basic research about anxiety and in applying it in clinical contexts. It is divided into four sections, covering general issues about anxiety (ethological and developmental ones), basic research issues on specific aspects of anxiety (bioanatomical ones, correlation with personality structure and so on), and new clinical and therapeutical proposals and hypothesis. Each author summarized the clinical importance of his work, underlining the clinical pitfalls of this publication.
Chapter
Fear is an important emotion for survival, and the cerebellum has been found to contribute not only to innate affective and defensive behavior, but also to learned fear responses. Acquisition and retention of fear conditioned bradycardia and freezing have been shown to depend on the integrity of the cerebellar vermis in rodents. There is a considerable number of brain imaging studies, which observe activation of the human cerebellum in fear conditioning paradigms. Different to what one may expect based on the initial cerebellar lesion studies, activations related to the learned prediction of threat go well beyond the vermis, and are most prominent in the lateral cerebellum. Different parts of the cerebellum likely contribute to learning of autonomic, motor, emotional and cognitive responses involved in classical fear conditioning. The neural operation which is performed in the various parts of the cerebellum is frequently assumed to be the same. One hypothesis is that the cerebellum acts as, or is part of, a predictive device. More recent findings will be discussed that the cerebellum may not only be involved in the processing of sensory prediction errors, but also in the processing of reward and reward prediction errors, which may play a central role in emotions and emotional learning. Current knowledge about the intrinsic learning mechanisms underlying fear memory in the cerebellum, and its connections with subcortical and cortical fear circuitry will be presented. The chapter will conclude with a discussion on how disordered cerebellar fear learning may contribute to affective disorders.
Article
Fragile X syndrome is the most important X-linked etiology of mental retardation and developmental disability currently known. Accumulating evidence also indicates that male and female carriers of the fragile X genetic abonormality demonstrate a relatively specific pattern of psychiatric disturbance. Fragile X males frequently manifest behaviors from the autistic spectrum whereas females show dysfunction in social interaction, thought processes, and affective regulation. In this review, an overview of the fragile X syndrome is presented with a focus on the occurrence of particular neuropsychiatric characteristics in males and females. Relevant data from recent genetic and neurobiological research is also described. The ability to study individuals with a specific genetic cause of psychopathology such as fragile X syndrome makes this condition of particular interest to biological psychiatry.
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I.M.J. LANGE, Z. KASANOVA, L. Goossens, N. Leibold, Chris I. De Zeeuw, T. van Amelsvoort, K. Schruers. The Anatomy of Fear Learning in the Cerebellum: A Systematic Meta-analysis. NEUBIOREV-D-14-00305. Recent neuro-imaging studies have implicated the cerebellum in several higher-order functions. Its role in human fear conditioning has, however, received limited attention. The current meta-analysis examines the loci of cerebellar contributions to fear conditioning in healthy subjects, thus mapping, for the first time, the neural response to conditioned aversive stimuli onto the cerebellum. By using the activation likelihood estimation (ALE) technique for analyses, we identified several distinct regions in the cerebellum that activate in response to the presentation of the conditioned stimulus: the cerebellar tonsils, lobules IV-VI, and the culmen. These regions have separately been implicated in fear acquisition, consolidation of fear memories and expression of conditioned fear responses. Their specific role in these processes may be attributed to the general contribution of cerebellar cortical networks to timing and prediction. Our meta-analysis highlights the potential role of the cerebellum in human cognition and emotion in general, and addresses the possibility how deficits in associative cerebellar learning may play a role in the pathogenesis of anxiety disorders. Future studies are needed to further clarify the mechanistic role of the cerebellum in higher order functions and neuropsychiatric disorders.
Chapter
Autism was first classified as a distinct disorder in 1943, when Leo Kanner identified 11 children who were differentiated from children with other disorders by the unusual characteristics they all shared. The behavioral features Kanner observed and described included a lack of communicative speech, language disturbances such as echolalia and pronoun reversal, excellent rote memory, difficulty in understanding abstract concepts, disturbances of nonverbal behavior (e.g., stereotyped behavior and lack of imaginary play), and an unawareness of other people, or “autistic aloneness” (Kanner, 1943). In addition, these children had displayed symptoms since infancy, had normal physical developmental histories, and appeared to be serious and intelligent.
Article
The Neuron-specific gene family (NSG1-3) consists of small endolysosomal proteins that are critical for trafficking multiple receptors and signaling molecules in neurons. NSG1 has been shown to play a critical role in AMPAR recycling from endosomes to plasma membrane during synaptic plasticity. However, to date nothing is known about whether NSG1 is required for normal behavior at an organismal level. Here we performed a battery of behavioral tests to determine whether loss of NSG1 would affect motor, cognitive, and/or affective behaviors, as well as circadian-related activity. Consistent with unique cerebellar expression of NSG1 among family members, we found that NSG1 was obligatory for motor coordination but not for gross motor function or learning. NSG1 knockout (KO) also altered performance across other behavioral modalities including anxiety-related and diurnal activity paradigms. Surprisingly, NSG1 KO did not cause significant impairments across all tasks within a given modality, but had specific effects within each modality. For instance, we found increases in anxiety-related behaviors in tasks with multiple stressors (e.g., elevation and exposure), but not those with a single main stressor (e.g., exposure). Interestingly, NSG1 KO animals displayed a significant increase in locomotor activity during subjective daytime, suggesting a possible impact on diurnal activity rhythms or vigilance. Surprisingly, loss of NSG1 had no effect on hippocampal-dependent learning despite previous studies showing deficits in CA1 long-term potentiation. Together, these findings do not support a role of NSG1 in hippocampal-dependent learning, but support a role in mediating proper neuronal function across amygdalar and cerebellar circuits.
Thesis
Le cervelet est une structure cérébrale impliquée dans de multiples fonctions motrices mais aussi cognitives et dont le développement postnatal est sous le contrôle de divers types de facteurs dont les neuropeptides. Les peptides capables d’agir sur le développement du cortex cérébelleux présentent généralement un profil d’expression particulier, avec chez le rongeur un pic d’expression au cours des 2 premières semaines postnatales. L’objectif de cette étude était d’identifier d’autres peptides présentant ce même type d’expression et de caractériser leurs potentiels effets au cours du développement du cortex cérébelleux, et plus particulièrement dans la mise en place des neurones en grain qui sont les plus abondants de cette structure. Pour cela, des cervelets de rats âgés de 8 à 90 jours ont été analysés par spectrométrie de masse. Parmi les 33 peptides identifiés, 4 présentent le profil recherché et nous avons choisi d’étudier l’un d’entre eux, la nociceptine. La mesure de l’expression du gène de la nociceptine et de son récepteur montre un profil d’expression similaire à celui observé en peptidomique. De plus, ces 2 gènes sont retrouvés principalement exprimés dans la couche granulaire interne du cortex cérébelleux par microdissection et qPcr. La recherche de la fonction de la nociceptine montre qu’elle exerce un effet neurotrophique en augmentant la survie et la différenciation des neurones en grain, sans affecter la motilité de ces cellules. Des tests préliminaires réalisés in vivo indiquent que la nociceptine est aussi capable de bloquer la toxicité induite par l’alcool. La dernière partie de l’étude avait pour but d’identifier de nouveaux neuropeptides exprimés dans le cervelet en utilisant une approche par séquençage de novo. L’application de filtres comme la récurrence des séquences peptidiques ou leur régulation au cours du développement a permis de ne retenir que 6 séquences pour la suite de l’analyse. Des études génomiques permettront de restreindre encore ce nombre afin de focaliser les tests d’activité biologique sur la ou les cibles qui ont la plus grande probabilité de correspondre à des peptides biologiquement actifs.
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Fear conditioning is a form of associative learning that is known to involve brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memory, indicating a role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. In addition, we found that a FN - thalamic parafascicular nucleus pathway, which may relay cerebellar influence to the amygdala, is involved in anxiety and fear expression but not in fear memory. Our results reveal the contributions to the emotional system of the cerebellum, which exerts a potent control on the strength of the fear memory through excitatory FN-vlPAG projections.
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Purkinje cells are the only output cell of the cerebellar cortex. Their spatiotemporal activity is controlled by molecular layer interneurons (MLIs) through GABAA receptor-mediated inhibition. Recently, it has been reported that the cerebellar cortex is required for consolidation of conditioned fear responses during fear memory formation. Although the relevance of MLIs during fear memory formation is currently not known, it has been shown that synapses made between MLIs and Purkinje cells exhibit long term plasticity following fear conditioning. The present study examined the role of cerebellar MLIs in the formation of fear memory using a genetically-altered mouse line (PC-∆γ2) in which GABAA receptor-mediated signaling at MLI to Purkinje cell synapses was functionally removed. We found that neither acquisition nor recall of fear memories to tone and context were altered after removal of MLI-mediated inhibition.
Article
In the last decade a growing body of data revealed that the cerebellum is involved in the regulation of the affective reactions as well as in forming the association between sensory stimuli and their emotional values. In humans, cerebellar areas around the vermis are activated during mental recall of emotional personal episodes and during learning of a CS-US association. Lesions of the cerebellar vermis may affect retention of a fear memory without altering baseline motor/autonomic responses to the frightening stimuli in both human and animal models. Reversible inactivation of the vermis during the consolidation period impairs retention of fear memory in rodents. Recent findings demonstrate that long-term potentiation (LTP) of synapses in the cerebellar cortex occurs in relation to associative fear learning similar to previously reported data in the hippocampus and amygdala. Plastic changes affect both excitatory and inhibitory synapses. This concomitant potentiation allows the cerebellar cortical network to detect coincident inputs, presumably conveying sensorial stimuli, with better efficacy by keeping the time resolution of the system unchanged. Collectively, these data suggest that the vermis participates in forming new CS-US association and translate an emotional state elaborated elsewhere into autonomic and motor responses.
Article
Social-emotional information processing (SEIP) is critical for appropriate human interaction. It is composed of processes that underlie how we behave towards others, especially in response to adverse social threat. We conducted a study in 26 healthy participants who completed a validated Video-SEIP (V-SEIP) task in the fMRI scanning environment. The V-SEIP phases studied included encoding (ENC) of socially relevant information, hostile attribution (HA) of motive, and the negative emotional response (NER) the participant would have in the context of the video vignettes. The ENC phase was associated with activation of amygdala, left ventrolateral prefrontal cortex, right middle temporal gyrus, and visual cortex, the HA phase associated with activation of several brain regions including frontal and temporal cortex as well as basal ganglia and cerebellum, while the NER phase was associated with activation in the midbrain with regions involving the periaqueductal gray, basal ganglia, and the cerebellum. We suggest that this V-SEIP task represents a novel neuro-biomarker for the study of SEIP and that it can be extended for use in a number of psychiatric conditions in which anger, irritability, and impulsive aggressive are prominent features.
Article
Increased prevalence of emotional distress is associated with tinnitus and hearing loss. The underlying mechanisms of the negative emotional response to tinnitus and hearing loss remain poorly understood, and it is challenging to disentangle the emotional consequences of hearing loss from those specific to tinnitus in listeners experiencing both. We addressed these questions in laboratory rats using three common rodent anxiety screening assays: elevated plus maze, open field test, and social interaction test. Open arm activity in the elevated plus maze decreased substantially after one trial in controls, indicating its limited utility for comparing pre- and post-treatment behavior. Open field exploration and social interaction behavior were consistent across multiple sessions in control animals. Individual sound-exposed and salicylate-treated rats showed a range of phenotypes in the open field, including reduced entries into the center in some subjects and reduced locomotion overall. In rats screened for tinnitus, less locomotion was associated with higher tinnitus scores. In salicylate-treated animals, locomotion was correlated with age. Sound-exposed and salicylate-treated rats also showed reduced social interaction. These results suggest that open field exploratory activity is a selective measure for identifying tinnitus distress in individual animals, whereas social interaction reflects the general effects of hearing loss. This animal model will facilitate future studies of the structural and functional changes in the brain pathways underlying emotional distress associated with hearing dysfunction, as well as development of novel interventions to ameliorate or prevent negative emotional responses.
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Data implicate the cerebellum (CB) in the regulation of sensory processes and autonomic functions and establish an influence of cerebellar systems on the regulation of emotional and motivational behaviors. The CB provides extensive projections to brain-stem and limbic mechanisms that have been implicated in behavioral regulation, and experimental manipulations of the CB have been found to profoundly affect behavioral processes. The present paper offers a conceptual view of cerebellar function that reconciles these apparently disparate actions. It is suggested that the CB exerts functionally similar influences at all levels of sensorimotor and behavioral organization. This model provides a conceptual framework for understanding the behavioral consequences of cerebellar dysfunctions, which can be viewed as behavioral parallels to the classical cerebellar motor syndromes. Data implicating cerebellar systems in the pathogenesis of developmental disturbances in behavioral processes (such as among autistic and hyperkinetic children) are considered in the context of the present conception of the CB's behavioral function. (3 p ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
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Rats received shocks in one apparatus, and post-shock “freezing” was then assessed in that apparatus or in a different one. The assessment of freezing was made immediately after shock or after a 24-hour delay. Post-shock freezing was reduced when the animals were tested in a different apparatus from that in which shocks had been administered. No reduction in freezing was caused by the 24-hour delay. All the post-shock freezing was therefore attributable to contextual cues and to generalization between contexts. This pattern of results suggests that post-shock freezing is entirely produced by conditioned fear elicited by cues associated with shock and that no part of post-shock freezing is an unconditional response (UR) directly elicited by shock.
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Bilateral lesions of the rat cerebellar dentate and lateral interposed nuclei produced transient deficits in movement and posture, and facilitated acquisition of two-way active avoidance. Bilateral lesions of the fastigial and medial interposed nuclei of the rat cerebellum also produced transient deficits in movement and posture, but impaired acquisition of the avoidance task. Analysis of degeneration patterns after unilateral lesions to either the lateral or medial nuclear region indicated that the lateral area has a denser rostral projection than the medial area, while the medial nuclear region has a heavier caudal projection. It is suggested that these differences in anatomic connections may be related to the observed differences in lesion effect on two-way active avoidance.
Article
Although the relationship between limbic system structures and emotionality is well known, the role of the cerebellum in the control of affective behavior is not usually appreciated (Berman, 1970a, b; 1971). Involvement of the limbic system in the elaboration of emotional behavior has been demonstrated by studies such as those of Kluver and Bucy (1939), Pribram and Bagshaw (1953) and Weiskrantz (1956), in which a taming effect was reported following amygdaloidectomy in the monkey. Reduced emotionality in the monkey has also been reported following cingulectomy (Glees, Cole, Whitty, & Cairns, 1950) and postero-medial orbital frontal cortex ablations (Butter, Snyder, & McDonald, 1970).
Article
An audiovisual stimulus was made contingent upon the rat’s licking at the water spout, thus making it analogous with a gustatory stimulus. When the audiovisual stimulus and the gustatory stimulus were paired with electric shock the avoidance reactions transferred to the audiovisual stimulus, but not the gustatory stimulus. Conversely, when both stimuli were paired with toxin or x-ray the avoidance reactions transferred to the gustatory stimulus, but not the audiovisual stimulus. Apparently stimuli are selected as cues dependent upon the nature of the subsequent reinforcer.
Article
Suggests that prevailing theories of avoidance learning and procedures used to study it are out of touch with what is known about how animals defend themselves in nature, and proposes an alternate assumption that animals have innate species-specific defense reactions (SSDRs) such as fleeing, freezing, and fighting. If a particular avoidance response is rapidly acquired, then that response must necessarily be an SSDR, hence, the learning mechanism appears to be suppression of nonavoidance behavior by the avoidance contingency. Traditional approaches to avoidance learning appear to be slightly more valid in the case of responses that are slowly acquired, although in this case, too, the SSDR concept is relevant, and reinforcement appears to be based on the production of a safety signal rather than the termination of an aversive CS. (53 ref.) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
Results from 3 experiments with 96 male albino rats indicate that lesions of the fastigial nuclei and cerebellar vermis, but not lesions of the dentate nuclei produced marked performance deficits on a differential reinforcement of low rates (DRL) schedule of reinforcement. This deficit was characterized by an abnormal number and distribution of responses within the schedule interval. Lesions, however, did not produce a deficit following preoperative training or when Ss were tested on an FI schedule. When DRL and FI performances were contrasted, all Ss were responsive to schedule contingencies. Results suggest that the DRL deficit following cerebellar lesions is due to a tendency to perseverate in response strategies and is not related to a global disruption of timing or a pervasive inability to suppress responding. (61 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
An approaching cat elicited active avoidance in albino rats. Rats also crossed an electrified grid to avoid an immobile cat. However, when confined with a cat, the rats' predominant response was freezing. These rats had never before encountered a cat, and no cat-rat tactile contact was necessary to produce either freezing or avoidance. The similarity of these reactions to responses elicited by stimuli previously associated with shock suggests that responses to conditioned fear stimuli are based on defensive reactions of adaptive value in the evolutionary history of the rat.
Article
Rats were given five shocks over a 5-min period and then observed for 20 min. Much more freezing was observed in animals that remained in the shock situation than in animals moved to another situation. Freezing, therefore, seems to be controlled primarily by external shock-related cues. Freezing appears to be also partly controlled by the inherent stimulus properties of the situation.
Article
The reactivity to electrical shock of control animals and animals with lesions of the cerebellar cortex was compared. At current levels above 200 μA no differences could be found between the groups. At threshold levels animals with lesions of the vermis showed the first measureable response to shock at significantly higher current levels than animals of the other two groups. The findings lend further support to the concept of a functional differentiation between the cerebellar cortex of the vermis and the hemispheres.
Article
An extensive stimulation mapping study of the rat cerebellum was carried out in 82 animals. It was found that complex oral behaviors (eating, grooming, and gnawing) as well as self-stimulation could be obtained from a region including the rostro-ventral anterior lobe vermis, fastigial nucleus, and superior cerebellar peduncle. The behaviors, differing in several respects from hypothalamic-elicited behaviors, appeared only in the presence of the appropriate goal object, thus ruling out simple motor automatisms. The present results suggest that the traditional view of the cerebellar role of improving the coordination of individual muscle movements and posture may need to be expanded. Indeed, the cerebellum may act to facilitate and coordinate complex chains of species-specific behavior patterns.
Article
Thirty-two of 53 rats receiving electrical stimulation of the cerebellum (ESC) displayed at least one stimulusbound response, and grooming was the most frequently evoked behavior. In the absence of any special procedures, only 4 animals exhibited any additional oral behaviors. However, 26 other animals that groomed during the stimulation also began to eat, gnaw wood, and/or drink water when goal objects were presented manually. The failure of these stimulated animals to approach goal objects on their own could not be explained by a lack of stimulation experience with relevant goal objects. ESC also inhibited male sexual behavior and eating in food deprived rats. In both these cases, competing responses (usually grooming) were elicited throughout the stimulation interval. Positive, negative, and neutral reinforcing effects were obtained from electrode sites supporting oral behaviors; but other sites yielded only neutral and negative effects. ESC was ineffective in eliciting object-carrying behavior.
Article
Reviews the literature to determine the involvement of the cerebellum in psychological processes. Traditional concepts of cerebellar physiology have emphasized motor control functions. It is suggested that this brain structure may participate in sensory integration activities, motor skills learning, visual and auditory discrimination performance, emotion and motivation control, and reinforcement processes. (6 p ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
The influence of the cerebellum on activity of the septal region, hippocampus, and amygdala of cats and rats was determined by obtaining unit recordings from those supratentorial sites with cerebellar stimulation. With stimulation of the postral vermis, fastigial nucleus, and intervening midline folia of the cerebellum, units in the septal region were facilitated, whereas those in the hippocampus were inhibited. Mixed results were obtained in the amygdala, some units being facilitated and others inhibited. Stimulation over the lateral cerebellar hemispheres and dentate nucleus, on the other hand, yielded no changes in activity, and stimulation of the posterior vermis produced inconsistent septal facilitation and no hippocampal response. With stimulation of the rostral cerebellar vermis and fastigial nucleus, evoked potentials at the supratentorial sites were of very short delay times, indicating direct pathways from the cerebellum to the septal region, hippocampus, and amygdala. When the dentate and fastigial nuclei were lesioned in cats, the firing rate of cells at supratentorial sites was not affected and cerebellar vermis stimulation did not significantly alter delay times of evoked responses, providing further evidence of a direct influence of the cerebellar vermis on the supratentorial sites. Relating these findings to previous patient and animal data provides a rationale for use of specific types of cerebellar simulation in the treatment of intractable behavioral disorders and epilepsy.
Article
Identification of brain sites where physiologic activity was correlated with subjective emotional experiences in patients undergoing treatment was the starting point for our investigations of the neural basis for emotion and related clinically documented behavioral phenomena. By use of anatomic and physiologic techniques, the neural substrate has been shown to be notably different from that which continues to be described in textbooks, that is, the limbic system. Establishing the neurophysiologic basis for emotion has led to effective treatment for some neurologic and psychiatric disorders. Further, it has provided a basis for defining the origin of certain clinical disorders that are still obscure, the first step toward development of their specific treatment.
Article
Cerebellar influences on the various substructures in the Papez Circuit are indicated by the following. 1. Anatomical studies indicate that the major midbrain areas to which this circuit projects are : 1) ventral tegmental area; 2) interpeduncular area; and 3) periaqueductal gray areas; and these same areas project back to the limbic system. There are projections to these regions from the cerebellar nuclei, as indicated by terminal degeneration studies which show that cerebellar nuclei connect, mostly by fine fibers, with a continuum of cells located on either side of the midline in the ventral tegmentum of the midbrain. Observations that the cerebellum also projects to the locus ceruleus (NA system) and VTA (DA system) indicate that cerebellar influences can also reach the limbic areas via the catecholamine fiber bundles. 2. Electrophysiological studies indicate that vermiam and fastigial stimulation induce evoked responses in the basolateral amygdala, the hippocampus, and the septum, with latencies to the peak of first wave ranging from 4 to 8 msec and to the second wave of 16-29 msec. Citations from the physiological literature indicate that electrical stimulation of the cerebellum, especially the vermis, can modify a wide range of responses which involve functional activities of either the sympathetic or parasympathetic nervous systems. 3. Studies on electrically induced afterdischarges in the septum, hippocampus, and amygdala indicate that cerebellar stimulation can shorten the duration of or terminate the afterdischarges, and the site of lowest threshold is the midline cortex. Focal cooling of the vermis promotes prolongation of the afterdischarges as does pretreatment of animals with 6-OH dopamine. Chemical lesions in the catecholamine system induced by 6-OH dopamine reduce the effectiveness of the cerebellar stimulation, as do lesions of nucleus fastigii. These data are interpreted to indicate that the cerebellum can exert a tonic suppressor (inhibitory?) influence on substructures within the Papez Circuit. 4. Citations from animal behavioral studies indicate that electrical stimulation of the anterior cerebellum can induce responses such as arousal, predatory attack, and feeding which mimic those obtained by amygdaloid stimulation. Fastigial stimulation can produce drowsiness and EEG changes which resemble the sleep patterns resulting from stimulation of the ventral amygdala.
Article
Two experiments were conducted to test the prediction that rats should react with reduced sensitivity/reactivity to nociceptive stimulation in the presence of a cat. In Experiment 1, naloxone or saline was administered, and rats were exposed to no stimulus, a novel stimulus, or a cat. In Experiment 2, rats were exposed to either no stimulus or a cat, and naltrexone was administered. In both experiments, rats tested in the presence of the cat showed a significant reduction in sensitivity/reactivity to a skin-irritating formalin injection. Naltrexone reversed this analgesia.
Article
The amygdala has been attributed with a considerable number of very diverse functions. Its involvement in learning and memory, though, has found increased attention. Following a short description of the connections of the amygdala and its critical neurotransmitters, studies are reviewed here in which the amygdala's activity was manipulated or observed by different methods (lesions, electrical brain stimulation, neurochemical intra-amygdaloid injections, single-unit recordings). Some of the major conclusions resulting from this data analysis indicate an advantage in performing subtotal amygdaloid lesions over an amygdalectomy, a point of view that is especially supported by the heterogeneous anatomical connections of different amygdaloid nuclei. Thereafter, an evaluation is made of different tasks with respect to their discriminative sensitivity to amygdaloid manipulations. Some species-specific differences in performing certain tasks after amygdaloid injuries are discussed in relation to the different expansion of amygdalo-cortical connections in higher and less highly encephalized species. Finally, some general assumptions are made on the specific role of each of the amygdaloid nuclei during the mnemonic processes attributed to the amygdala. It is concluded that emotionally significant information is encoded and can be retrieved on the basis of the structures and connections of the basolateral limbic circuit.
Article
Reports results of 8 experiments with a total of 327 male Sprague-Dawley rats. Lesions to the basolateral amygdala produced permanent impairment in Ss' ability to learn a taste aversion. When lesions were administered after Ss had already learned an aversion, there was complete loss of the aversion. Ss with amygdala lesions also had a diminished neophobic response when presented with a novel solution and showed a more generalized aversion to water after a sucrose-sickness trial. Whether a solution was novel or familiar affected the learning of an aversion for controls more than it did for Ss with amygdala lesions. Ss with amygdala damage also showed less sodium appetite than normals in response to desoxycorticosterone acetate injections. These results indicate that rats with amygdala lesions have deficits in recognizing the significance of stimuli. (49 ref)
Article
Whereas the notion was generally accepted in the last half century that the cerebellum was mainly concerned with movement control, very recent evidence is reviewed that strongly suggests cerebellar involvement in emotional behavior, epileptic seizure control and autonomic nervous function.
Article
Lesions of the cerebellar vermis in cats and monkeys were found to have a taming effect. The lesions extended from the declive to the pyramis and produced slight but persistent changes in some aspects of motor behavior.
Article
Studied thigmotaxis (i.e., the tendency to run in contact with objects) in 3 experiments with a total of 54 female Long-Evans rats. Exp. I indicated that Ss became more thigmotactic and immobile following shock compared with no-shock conditions. Exp. II demonstrated that when 2 groups were required to make comparable, but different, avoidance responses, the group whose avoidance response was more closely related to the S's species-specific defensive behavior was acquired at a faster rate. The 3rd experiment indicated that the differences in the acquisition of the avoidance responses in Exp. II were not due to differences in operant rates for the 2 responses per se, since acquisition of these same 2 responses was similar under appetitive motivation.
Article
Gave 8 male albino rats control operations and 10 Ss large radio-frequency lesions of the amygdaloid area. Lesioned Ss showed reduced freezing to an immobile cat or to previously neutral stimuli associated with footshock. These Ss also failed to avoid either the immobile cat or an approaching shock prod. In a 2nd experiment with 16 Ss, smaller electrolytic lesions, largely involving the corticomedial amygdaloid nuclei, produced similar results. This pattern of alterations of reactivity to unconditioned and conditioned threat stimuli suggests that the amygdaloid area has a central role in the regulation of defensive reactions.
Article
The effects of strain, sex, and level of illumination on open-field behavior were investigated with black-hooded and agouti-selfed rats. Results indicated that (a) black-hooded rats locomote more, rear equally often, and are less prone to leave the peripheral wall (more thigmotaxic) than agoutiselfed rats; (b) female rats locomote more, rear more, but show the same degree of thigmotaxis as males; and (c) increases in illumination produce decreases in both locomotion and rearing but increases in thigmotaxis.
Article
A direct hypothalamocerebellar projection in the cat was revealed by means of retrograde transport of wheat germ agglutinin--horseradish peroxidase complex. This appears to be the first demonstration of a significant autonomic input to the cerebellum. The projection has a widespread origin and is bilateral with an ipsilateral preponderance.
Article
Neural regions which exercise an inhibitory influence on agonistic behavior are identified by the enhancement of agonistic behavior that follows their removal. The specific kinds of agonistic behaviors altered by each region are then examined. Increased reactivity to the experimenter and enhanced shock-induced fighting are produced by lesions of the region ventral to the anterior septum, the lateral septum, the medial hypothalamus, and the dorsal and median raphe nuclei. It is argued that the increased reactivity and shock-induced fighting correspond to an enhancement of defensive behavior. Mouse killing is induced by lesions of the anterior olfactory nucleus, the region ventral to the anterior septum, the lateral septum, the medial hypothalamus, the dorsal and median raphe nuclei, and the medial amygdala. Because the lesion-induced mouse killing is similar to that emitted by spontaneous mouse killers, it is argued that these regions normally exert an inhibitory control over predatory killing. The available evidence on social attack behavior has not convincingly identified regions exerting an inhibitory control over this dimension of behavior. Our conclusion is that separate brain systems exert an inhibitory control over defensive behavior, predatory killing, and social attack behavior. To a substantial extent, the regions modulating these behaviors appear to act independently of one another. The only neurotransmitter that is clearly active in these inhibitory systems is serotonin, and has only been directly implicated in the control of mouse killing by neurons originating in the dorsal and median raphe nuclei.
Article
Lesions of the cerebellar fastigial nucleus were found to greatly attenuate the hyperemotionality produced by simultaneous septal lesions in the rat. Lesions dorsal or lateral to the fastigial nucleus had no effect. This lesion-related attenuation of emotionality produced by fastigial destruction appeared quite specific. Other motivated behaviors such as food intake and activity were not affected. Further, the characteristic increase in social contacts seen after septal destruction was not altered by the fastigial lesions. The results support the view that the cerebellar fastigial nucleus is part of a complex limbic-brainstem network involved in the control of emotional and motivational behaviors.
Article
In rats, lesions of the cerebellar fastigial nucleus, but not lateral nuclear lesions or cerebellar cortical lesions, resulted in significant reductions in activity, open-field exploratory behavior, and social interactions. These deficits showed no recovery over a 4-wk testing period and were not related to the motor effects of the lesions. Other motivated behaviors, such as eating, grooming, gnawing, and pain responsiveness, were minimally affected. This pattern of results, together with other findings, suggests the existence of two separate fastigial output pathways to neurobehavioral substrates. One of these is the direct fastigio-bulbar pathway, which mediates the eating, grooming, and gnawing behaviors elicited by fastigial stimulation. The other is the ascending fastigial projection to limbic structures, which may mediate fastigial influences on activity and social interaction.
Article
Examines the use in the literature of the open-field test, especially with regard to the development of a standard form. The various procedures and their shortcomings are discussed, with particular reference to the seemingly inconsequential details which have been shown to modulate open-field performance per se. Dependent parameters are considered both with regard to their reliability and their validity for the measurement of such underlying constructs as emotionality. (92 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Innate and conditioned agonistic behavior in the rat: A review
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Blanchard, R. J. and D. C. Blanchard. Innate and conditioned agonistic behavior in the rat: A review. Neurosci Biobehav Rev 6: 125-143, 1982.
Defensive reactions in the albino rat reactions to threat in rats with amygdaloid lesions
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The Cerebellum and Neural Control The effect of previous experience upon operant performance following cerebellar lesions in the rat
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A Stereotaxic Atlas of the Rat Brain
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Cerebellar projections to the Papez circuit
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