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Effects of lesions of the cerebellar vermis on VMH lesion-induced hyperdefensiveness, spontaneous mouse killing, and freezing in rats

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Abstract

In a series of independent experiments, we showed that lesions of the vermis of the cerebellum in rats blocked the hyperdefensiveness induced by lesions of the ventromedial hypothalamus (VMH), attenuated spontaneous mouse killing, and reduced unconditioned freezing and other signs of fear in the presence of a cat. The vermal lesions did not significantly affect foot-shock conditioned freezing. Control lesions of the cerebellar hemispheres did not affect VMH lesion-induced hyperdefensiveness or freezing in the presence of a cat. The hemispheric lesions did attenuate foot-shock conditioned freezing. The data are discussed in terms of the striking similarities and differences between the behavioral effects of cerebellar vermal lesions and amygdala lesions and the interaction of a number of brain areas in modulating agonistic behaviors. The results leave no doubt that the medial cerebellum is significantly involved in the control of species-specific agonistic behaviors. The specific dimension of agonistic behaviors and the details of the interactions with other brain areas remain a puzzle which we approached here by expanding the behavioral profile of animals with lesions of the cerebellar vermis.

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... Anatomically, the medial cerebellar nucleus (mCbN in rodents; the fastigial nucleus in primates), which receives input from the cerebellar vermis, projects to the vlPAG (Teune et al., 2000;Gonzalo-Ruiz et al., 1990). Although this projection has been attributed primarily to oculomotor function, lesions of the cerebellar vermis lead to decreases in both innate and conditioned freezing in rodents (Supple et al., 1988;Koutsikou et al., 2014;Sacchetti et al., 2002). Given known roles of the cerebellum in sensorimotor integration, it seems plausible that it may participate in perception of potential threats, prediction of threat probability, and/or execution of innate or conditioned freezing behavior. ...
... We reasoned that the influence of the cerebellar vermis on innate freezing (Supple et al., 1988;Koutsikou et al., 2014) might result from direct synaptic connections in the ventrolateral periaqueductal gray. Previous tracing studies have demonstrated that the mCbN indeed projects to the vlPAG (Gonzalo-Ruiz et al., 1990;Teune et al., 2000), and electrical stimulation of the mCbN elicits short latency field potentials in the vlPAG (Whiteside and Snider, 1953), but this projection has historically been thought to contribute to oculomotor function. ...
... Given that Purkinje cells inhibit mCbN cells, along with the observation that lesions of the cerebellar vermis reduce innate freezing (Supple et al., 1988;Koutsikou et al., 2014), the simplest prediction is that mCbN input might suppress the activity of Chx10 cells. Such an effect might be achieved by direct inhibition of Chx10 cells, since a subset of mCbN cells have been reported to be glycinergic (Bagnall et al., 2009) or by excitation of other neurons that lead to a decrease in Chx10 cell activity. ...
Article
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Innate defensive behaviors, such as freezing, are adaptive for avoiding predation. Freezing-related midbrain regions project to the cerebellum, which is known to regulate rapid sensorimotor integration, raising the question of cerebellar contributions to freezing. Here, we find that neurons of the mouse medial (fastigial) cerebellar nuclei (mCbN), which fire spontaneously with wide dynamic ranges, send glutamatergic projections to the ventrolateral periaqueductal gray (vlPAG), which contains diverse cell types. In freely moving mice, optogenetically stimulating glutamatergic vlPAG neurons that express Chx10 reliably induces freezing. In vlPAG slices, mCbN terminals excite ~20% of neurons positive for Chx10 or GAD2 and ~70% of dopaminergic TH-positive neurons. Stimulating either mCbN afferents or TH neurons augments IPSCs and suppresses EPSCs in Chx10 neurons by activating postsynaptic D2 receptors. The results suggest that mCbN activity regulates dopaminergic modulation of the vlPAG, favoring inhibition of Chx10 neurons. Suppression of cerebellar output may therefore facilitate freezing.
... Anatomically, the medial cerebellar nucleus (mCbN in rodents; the fastigial nucleus in primates), which receives input from the cerebellar vermis, projects to the vlPAG (Teune et al., 2000;Gonzalo-Ruiz et al., 1990). Although this projection has been attributed primarily to oculomotor function, lesions of the cerebellar vermis lead to decreases in both innate and conditioned freezing in rodents (Supple et al., 1988;Koutsikou et al., 2014;Sacchetti et al., 2002). Given known roles of the cerebellum in sensorimotor integration, it seems plausible that it may participate in perception of potential threats, prediction of threat probability, and/or execution of innate or conditioned freezing behavior. ...
... We reasoned that the influence of the cerebellar vermis on innate freezing (Supple et al., 1988;Koutsikou et al., 2014) might result from direct synaptic connections in the ventrolateral periaqueductal gray. Previous tracing studies have demonstrated that the mCbN indeed projects to the vlPAG (Gonzalo-Ruiz et al., 1990;Teune et al., 2000), and electrical stimulation of the mCbN elicits short latency field potentials in the vlPAG (Whiteside and Snider, 1953), but this projection has historically been thought to contribute to oculomotor function. ...
... Given that Purkinje cells inhibit mCbN cells, along with the observation that lesions of the cerebellar vermis reduce innate freezing (Supple et al., 1988;Koutsikou et al., 2014), the simplest prediction is that mCbN input might suppress the activity of Chx10 cells. Such an effect might be achieved by direct inhibition of Chx10 cells, since a subset of mCbN cells have been reported to be glycinergic (Bagnall et al., 2009) or by excitation of other neurons that lead to a decrease in Chx10 cell activity. ...
Article
Full-text available
Innate defensive behaviors, such as freezing, are adaptive for avoiding predation. Freezing-related midbrain regions project to the cerebellum, which is known to regulate rapid sensorimotor integration, raising the question of cerebellar contributions to freezing. Here, we find that neurons of the mouse medial (fastigial) cerebellar nuclei (mCbN), which fire spontaneously with wide dynamic ranges, send glutamatergic projections to the ventrolateral periaqueductal gray (vlPAG), which contains diverse cell types. In freely moving mice, optogenetically stimulating glutamatergic vlPAG neurons that express Chx10 reliably induces freezing. In vlPAG slices, mCbN terminals excite ~20% of neurons positive for Chx10 or GAD2 and ~70% of dopaminergic TH-positive neurons. Stimulating either mCbN afferents or TH neurons augments IPSCs and suppresses EPSCs in Chx10 neurons by activating postsynaptic D2 receptors. The results suggest that mCbN activity regulates dopaminergic modulation of the vlPAG, favoring inhibition of Chx10 neurons. Suppression of cerebellar output may therefore facilitate freezing.
... 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). ...
Article
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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.
... 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.
... 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.
... In parallel with the present experiment, sectioning of the cerebellar peduncles was performed 24-48 h after acquisition. Injection of pertussis toxin in IN did not affect FPS 5 nor did injection of an NMDA receptor antagonist into IN affect extinction of FPS. 6 Vermal lesions that significantly reduced a rat's freezing in the presence of a cat did not affect context freezing to footshock, 7 and vermal lesions that blocked heart rate conditioning did not affect freezing to an auditory CS. 8 In this latter experiment, lesions to the cerebellar hemispheres were without affect on either heart rate conditioning or freezing to the auditory CS. ...
... On the other hand, VE lesions block heart rate conditioning and some forms of unconditioned freezing without affecting eyeblink conditioning. [7][8][9] Given the consistency of these outcomes, it is not clear why IN and VE should play similar roles in the consolidation of conditioned freezing to an auditory CS. Some dissociation, other than the context effect, would bring the present data in closer correspondence with existing cerebellar data. ...
Article
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The very long-term consolidation intervals shown by Sacchetti et al1 following inactivation of the cerebellum with tetrodotoxin (TTX) are quite remarkable. The intervals are consistent with intervals of up to 8 days previously reported by this group following inactivation of perirhinal cortex with TTX.2 The effects appear experimentally sound and robust. The authors persuade us that the outcomes are the result of 'the amnesic effect of the functional inactivation performed during consolidation.' The case is well made for the importance of the single-session procedure, the advantage of the acute stereotaxic procedure rather than the chronic cannulation procedure, and the freedom of their procedure from effects due to interference with motor or sensory processes. This latter point seems particularly critical when dealing with the cerebellum.
... 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). In addition, lesions of the anterior vermis are known to severely impair the acquisition and retention of the Pavlovian fear conditioned bradycardia, without altering unconditioned heart responses in rabbits and rats Supple & Leaton, 1990a;. ...
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.
... 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".
... In addition, the projections of the cerebellum to the brainstem regions relevant to visceral regulation have also been documented (Homma et al., 1995; Teune et al., 2000). Although several studies support that the FPR seems to be relative to the multi-synaptic projections of cerebellum to brainstem (Bradley et al., 1987; Homma et al., 1995; Reis and Golanov, 1997), the autonomic responses evoked by stimulating cerebellum were abolished following a precollicular decerebration (Zanchetti and Zoccolini, 1954; Supple et al., 1988). Thus, it is imperfect that the explanation for the cerebellar modulation on various visceral activities is simply mediated the cerebello–brainstem pathways . ...
Article
The cerebellum has been considered only as a classical subcortical center for motor control. However, accumulating experimental and clinical evidences have revealed that the cerebellum also plays an important role in cognition, for instance, in learning and memory, as well as in emotional behavior and in nonsomatic activities, such as visceral and immunological responses. Although it is not yet clear through which pathways such cerebellar nonsomatic functions are mediated, the direct bidirectional connections between the cerebellum and the hypothalamus, a high autonomic center, have recently been demonstrated in a series of neuroanatomical investigations on a variety of mammals and indicated to be potential pathways underlying the cerebellar autonomic modulation. The direct hypothalamocerebellar projections originate from the widespread hypothalamic nuclei/areas and terminate in both the cerebellar cortex as multilayered fibers and the cerebellar nuclei. Immunohistochemistry studies have offered fairly convincing evidence that some of these projecting fibers are histaminergic. It has been suggested that through their excitatory effects on cerebellar cortical and nuclear cells mediated by metabotropic histamine H(2) and/or H(1) receptors, the hypothalamocerebellar histaminergic fibers participate in cerebellar modulation of somatic motor as well as non-motor responses. On the other hand, the direct cerebellohypothalamic projections arise from all cerebellar nuclei (fastigial, anterior and posterior interpositus, and dentate nuclei) and reach almost all hypothalamic nuclei/areas. Neurophysiological and neuroimaging studies have demonstrated that these connections may be involved in feeding, cardiovascular, osmotic, respiratory, micturition, immune, emotion, and other nonsomatic regulation. These observations provide support for the hypothesis that the cerebellum is an essential modulator and coordinator for integrating motor, visceral and behavioral responses, and that such somatic-visceral integration through the cerebellar circuitry may be fulfilled by means of the cerebellar-hypothalamic circuits.
... Altered CV activity may reflect homeostatic or compensatory adaptation in RELS which confers resilience to cognitive and emotional deficits seen in BD, consistent with the relationship of cerebellar volume and resilience to mood disorder in RELS (63). Indeed, the CV participates in regulation of the midbrain/VTA-amygdala/parahippocampal components of the Papez circuit (67)(68)(69)(70)(71)(72)(73), and plays a strong role in regulation of emotion (74)(75)(76)(77)(78)(79), long-term fear conditioning (80,81), and Pavlovian conditioned cardiac responses (82,83), even independent of the amygdala (81). Further, CV transcranial magnetic stimulation (a putative treatment for mood disorders) directly affects amygdala/hippocampal activity (73). ...
Article
In this report, we seek to (i) identify a potential neuroimaging endophenotype for bipolar disorder (BD) in emotion regulatory and autonomic circuitry in young first-degree relatives of persons with BD; and (ii) replicate our previous work identifying the functional neuroanatomy of working memory (WM) in an older sample of relatives of persons with BD. Ten adolescent and young adult (age 13-24) unmedicated, non-ill, first-degree relatives of persons with BD (RELS) and 10 demographically comparable healthy controls performed a 2-back WM task and a 0-back control task during functional magnetic resonance imaging (fMRI). fMRI data were collected on a 1.5 Tesla scanner and analyzed using SPM-2. Mood was assessed on the day of scanning. The groups did not differ on any demographic, neuropsychological, or in-scanner task performance variables. In contrast to controls, RELS showed (i) weak task-dependent modulation activity in the cerebellar vermis (CV), insula, and amygdala/parahippocampal region, and (ii) exaggerated modulation of activity in the frontopolar cortex and brainstem, even after controlling for potential confounders. Many of the group differences were driven by differences in activity in the low-level (0-back) baseline task. Young, unmedicated RELS exhibited altered task-dependent modulation of frontopolar, CV, and insula activity during WM, especially during the low-level (0-back) baseline task. Results are largely consistent with our initial study of older adult RELS, suggesting these alterations may represent biomarkers of genetic risk for BD.
... Rich et al. (2008) reported abnormalities in connectivity to temporal association cortex in paediatric bipolar disorder, suggested to contribute to early abnormalities in misperception of social face cues in the disorder. The cerebellum also has substantial interconnections with the OPC (Anand et al., 1959; Snider et al., 1976; Ramnani, 2006), has been implicated in affective functions, and cerebellar lesions have been associated with manic-like symptoms (Yadalam et al., 1985; Supple et al., 1987 Supple et al., , 1988 Lauterbach, 1996; Schmahmann et al., 1998; Tavano et al., 2007). Neuroimaging studies of bipolar disorder have reported both structural and functional abnormalities in the cerebellum (DelBello et al., 1999; Ketter et al., 2001; Strakowski et al., 2005; Malhi et al., 2007; Womer et al., 2009b ). ...
Article
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The olfactocentric paralimbic cortex plays a critical role in the regulation of emotional and neurovegetative functions that are disrupted in core features of bipolar disorder. Adolescence is thought to be a critical period in both the maturation of the olfactocentric paralimbic cortex and in the emergence of bipolar disorder pathology. Together, these factors implicate a central role for the olfactocentric paralimbic cortex in the development of bipolar disorder and suggest that abnormalities in this cortex may be expressed by adolescence in the disorder. We tested the hypothesis that differences in olfactocentric paralimbic cortex structure are a morphological feature in adolescents with bipolar disorder. Subjects included 118 adolescents (41 with bipolar disorder and 77 healthy controls). Cortical grey matter volume differences between adolescents with and without bipolar disorder were assessed with voxel-based morphometry analyses of high-resolution structural magnetic resonance imaging scans. Compared with healthy comparison adolescents, adolescents with bipolar disorder demonstrated significant volume decreases in olfactocentric paralimbic regions, including orbitofrontal, insular and temporopolar cortices. Findings in these regions survived small volume correction (P < 0.05, corrected). Volume decreases in adolescents with bipolar disorder were also noted in inferior prefrontal and superior temporal gyri and cerebellum. The findings suggest that abnormalities in the morphology of the olfactocentric paralimbic cortex may contribute to the bipolar disorder phenotype that emerges in adolescence. The morphological development of the olfactocentric paralimbic cortex has received little study. The importance of these cortices in emotional and social development, and support for a central role for these cortices in the development of bipolar disorder, suggest that study of the development of these cortices in health and in bipolar disorder is critically needed.
... Any contribution of a general motor impairment was further reduced by the remarkable recovery of rats after these large vermal lesions. We have found in all of our experience with rats with vermal lesions of similar size and location (Leaton & Supple, 1986; Supple, Cranney, & Leaton, 1988; Supple et al., 1987) that the animals are ataxic and show marked rigidity and tremor of the limbs, particularly the hindlimbs, when they first recover from the anesthesia. These effects are reduced dramatically by the 3rd postoperative day and are absent by the time of testing. ...
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Three experiments assessed the effects of damage to the medial cerebellum on long-term habituation (LTH) of the acoustic startle response. Experiment 1 replicated previous results. Lesions of the cerebellar vermis blocked LTH without affecting initial response levels or short-term habituation (STH). The lesions did not disrupt LTH of a simultaneously measured lick-suppression response. In Experiment 2, vermal lesions again blocked LTH of acoustic startle. Control lesions of the cerebellar hemispheres did not affect LTH. In Experiment 3, lesions to the medial (fastigial) cerebellar nuclei blocked LTH. Lesions to the lateral (dentate and interpositus) nuclei did not affect LTH. It is concluded that the medial cerebellum (cortex and nuclei) is part of the essential circuitry for LTH of acoustic startle, whereas the lateral cerebellum is not involved in the basic habituation process.
... The studies by Maschke et al. (2002) and by Turner et al. (2007) suggest that the vermis in necessary to learn a new association between sensory stimuli and aversive ones, while it is not required for the regulation of baseline fear responses and for the cognitive evaluation of a dangerous situation. In line with this observation, animals with vermal lesion (Supple et al., 1987(Supple et al., , 1988 and the hotfoot mutant mice (Sacchetti et al., 2004) remember the environment (context) in which a painful stimulation is administered. Context representation is a form of hippocampal-dependent learning that resembles the human capacity to learn the declarative aspects of an emotional situation. ...
Article
Fear conditioning involves learning that a previously neutral stimulus (CS) predicts an aversive unconditioned stimulus (US). Lesions of the cerebellar vermis may affect fear memory without altering baseline motor/autonomic responses to the frightening stimuli. Reversible inactivation of the vermis during the consolidation period impairs retention of fear memory. In patients with medial cerebellar lesions conditioned bradycardia is impaired. In humans, cerebellar areas around the vermis are activated during mental recall of emotional personal episodes, if a loved partner receives a pain stimulus, and during learning of a CS-US association. Moreover, patients with cerebellar stroke may fail to show overt emotional changes. In such patients, however, the activity of several areas, including ventromedial prefrontal cortex, anterior cingulate, pulvinar and insular cortex, is significantly increased relative to healthy subjects when exposed to frightening stimuli. Therefore, other structures may serve to maintain fear response after cerebellar damage. These data indicate that the vermis is involved in the formation of fear memory traces. We suggest that the vermis is not only involved in regulating the autonomic/motor responses, but that it also participates in forming new CS-US associations thus eliciting appropriate responses to new stimuli or situations. In other words, the cerebellum may translate an emotional state elaborated elsewhere into autonomic and motor responses.
... Cerebellum-The cerebellum has anatomical connections to the amygdala-anterior paralimbic system (111)(112)(113)(114). The role of the cerebellum, and particularly of the vermis, in emotional behaviors is increasingly recognized, and individuals with cerebellar lesions have been noted to have BD-type symptoms (33,(115)(116)(117)(118)(119). DelBello et al. pioneered neuroimaging work in the cerebellum in BD, demonstrating volume abnormalities in the cerebellar vermis associated with the number of prior affective episodes (120-122) as well as family history of BD (123). ...
Article
In past decades, neuroimaging research in bipolar disorder has demonstrated a convergence of findings in an amygdala-anterior paralimbic cortex neural system. This paper reviews behavioral neurology literature that first suggested a central role for this neural system in the disorder and the neuroimaging evidence that supports it. Relevant articles are reviewed to provide an amygdala-anterior paralimbic cortex neural system model of bipolar disorder, including articles from the fields of behavioral neurology and neuroanatomy, and neuroimaging. The literature is highly supportive of key roles for the amygdala, anterior paralimbic cortices, and connections among these structures in the emotional dysregulation of bipolar disorder. The functions subserved by their more widely distributed connection sites suggest that broader system dysfunction could account for the range of functions-from neurovegetative to cognitive-disrupted in the disorder. Abnormalities in some components of this neural system are apparent by adolescence, while others, such as those in rostral prefrontal regions, appear to progress over adolescence and young adulthood, suggesting a neurodevelopmental model of the disorder. However, some findings conflict, which may reflect the small sample sizes of some studies, and clinical heterogeneity and methodological differences across studies. Consistent with models derived from early behavioral neurology studies, neuroimaging studies support a central role for an amygdala-anterior paralimbic neural system in bipolar disorder, and implicate abnormalities in the development of this system in the disorder. This system will be an important focus of future studies on the developmental pathophysiology, detection, treatment, and prevention of the disorder.
... Cerebellar syndromes that affect adult humans (e.g., hereditary ataxias) can often be devastating in their effects on normal functioning. Cerebellar lesions in adult rats cause any number of behavioral alterations [6,23,28,29,31,38,52]. Here, a known developmental cerebellar toxicant appeared to leave most behaviors intact in adult rats [19]. ...
Article
Developmental difluoromethylornithine (DFMO) treatment reduces cerebellar weight [Neuroscience 17 (1986) 399, Neurotoxicol. Teratol. 22 (2000) 415, Behav. Brain Res. 126 (2001) 135], but the functional alterations resulting from this have been little investigated. Here, Sprague-Dawley rats were subcutaneously injected with 500 mg/kg DFMO on postnatal days (PNDs) 5-12 and a comprehensive set of behavioral assessments measured early developmental behaviors (righting reflex, negative geotaxis), motor coordination, acoustic startle, short- and long-term activity, social behaviors, anxiety, and spatial learning and memory. DFMO treatment appeared to cause a decreased latency to perform the negative geotaxis behavior on PNDs 8-10 and increased latency to hang by the forelimbs on PNDs 12-14. Our previous study did not indicate similar effects, but age at testing differed between the two studies. DFMO treatment caused a decreased latency to maximum acoustic startle response in both the acoustic startle paradigm and in the pulse-alone trials of the prepulse inhibition test. This DFMO treatment paradigm induced a 10% decrease in adult cerebellar weight [Behav. Brain Res. 126 (2001) 135], but the results here imply that such developmental stunting has few functional alterations.
... Physiological and anatomical evidences suggest that the cerebellum can exert an influence on systems concerned with emotion (e.g., noradrenergic projections between locus caeruleus and the cerebellar vermis; Somana and Walberg, 1978). The cerebellar vermis also has a critical role in animal models of fear conditioning (Ghelarducci and Sebastiani, 1997; Sacchetti et al., 2002; Supple and Leaton, 1990; Supple et al., 1987 Supple et al., , 1988 Supple et al., , 1993). Finally, the human cerebellar vermis is also activated during the anticipation of aversive stimuli (Ploghaus et al., 2000). ...
Article
Making predictions about future rewards is an important ability for primates, and its neurophysiological mechanisms have been studied extensively. One important approach is to identify neural systems that process errors related to reward prediction (i.e., areas that register the occurrence of unpredicted rewards and the failure of expected rewards). In monkeys that have learned to predict appetitive rewards during reward-directed behaviors, dopamine neurons reliably signal both types of prediction error. The mechanisms in the human brain involved in processing prediction error for monetary rewards are not well understood. Furthermore, nothing is known of how such systems operate when rewards are not contingent on behavior. We used event-related fMRI to localize responses to both classes of prediction error. Subjects were able to predict a monetary reward or a nonreward on the basis of a prior visual cue. On occasional trials, cue-outcome contingencies were reversed (unpredicted rewards and failure of expected rewards). Subjects were not required to make decisions or actions. We compared each type of prediction error trial with its corresponding control trial in which the same prediction did not fail. Each type of prediction error evoked activity in a distinct frontotemporal circuit. Unexpected reward failure evoked activity in the temporal cortex and frontal pole (area 10). Unpredicted rewards evoked activity in the orbitofrontal cortex, the frontal pole, parahippocampal cortex, and cerebellum. Activity time-locked to prediction errors in frontotemporal circuits suggests that they are involved in encoding the associations between visual cues and monetary rewards in the human brain.
... The studies byMaschke et al. (2002)and byTurner et al. (2007)suggest that the vermis in necessary to learn a new association between sensory stimuli and aversive ones, while it is not required for the regulation of baseline fear responses and for the cognitive evaluation of a dangerous situation. In line with this observation, animals with vermal lesion (Supple et al., 1987Supple et al., , 1988) and the hotfoot mutant mice (Sacchetti et al., 2004) remember the environment (context) in which a painful stimulation is administered. Context representation is a form of hippocampal-dependent learning that resembles the human capacity to learn the declarative aspects of an emotional situation. ...
Conference Paper
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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.
... In humans, cerebellar disorders produce different kinds of motor impairments [9], and cerebellar lesions are correlated with the loss of accurate movements such as the opening of fingers when releasing a ball during throwing [10], or the failure to adapt arm movements for the purpose of adjusting the hand when catching balls with different weights [11]. In rats, the lesion of specific cerebellar pathways alters not only motor patterns, but also spatial learning during rota-rod and Morris water maze tests [12], and the lesion of the vermis alters agonistic behaviors [13] and autonomic responses related to heart rate [14]. In addition to presenting important information, these studies provide significant value to paradigms of experimentally controlled lesions to further understand the topographical localization of the cerebellar basis of behavior [12], particularly the sexual aspect in our case. ...
... Converging lines of evidence has suggested that the cerebellum is essential to distributed neural circuits involved in emotion and affect, particularly fear-related processes ( Schmahmann, 2013 ). For instance, cerebellum lesion attenuated a variety of fear-related behavior, such as the freezing behavior of a rat in the presence of a cat ( Supple et al., 1988 ). Consistent with this effect, the fear-related response is elicited by cerebellum stimulation (Moreno-Rius and Josep, 2018 ;Sacchetti et al., 2010 ). ...
Article
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Processing of fear is of crucial importance for human survival and it can generally occur at explicit and implicit conditions. It is worth noting that explicit and implicit fear processing produces different behavioral and neurophysiological outcomes. The present study capitalizes on the Activation Likelihood Estimation (ALE) method of meta-analysis to identify: (a) the “core” network of fear processing in healthy individuals; (b) common and specific neural activations associated with explicit and implicit processing of fear. Following PRISMA guidelines, a total of 92 fMRI and PET studies were included in the meta-analysis. The overall analysis show that the core fear network comprises the amygdala, pulvinar, and fronto-occipital regions. Both implicit and explicit fear processing activated amygdala, declive, fusiform gyrus, and middle frontal gyrus, suggesting that these two types of fear processing share a common neural substrate. Explicit fear processing elicited more activations at the pulvinar and parahippocampal gyrus, suggesting visual attention/orientation and contextual association play important roles during explicit fear processing. In contrast, implicit fear processing elicited more activations at the cerebellum-amygdala-cortical pathway, indicating an ‘alarm’ system underlying implicit fear processing. These findings have shed light on the neural mechanism underlying fear processing at different levels of awareness.
... 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.
... 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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... Notably, however, the cerebellum is often overlooked in models outlining the neural circuitry underlying fear-based responses to predators. Studies on rats with vermal cerebellar lesions reveal reduced unconditioned freezing responses in the presence of a cat, 3,26 where the vermis is thought to connect to the dlPAG via the fastigial nucleus and the SC, perhaps modulating activation of the dlPAG. ...
Article
Background: In lieu of consciously appraising the threat via cortical sensory processing, a subcortical ‘innate alarm system’ originating in the superior colliculus (SC) may activate innate defensive responses when threat is imminent. Individuals with posttraumatic stress disorder (PTSD) demonstrate supra- and subliminal threat detection, together contributing to hyperarousal symptoms and increased defensive responses. Here, the periaqueductal gray (PAG) may work in tandem with the SC to initiate instinctual defensive strategies. The current study was designed to examine functional connectivity patterns with the PAG and the SC at rest in PTSD and healthy controls. Methods: We examined PAG and SC resting-state functional connectivity in PTSD (n5107) and healthy controls (n561) using a seed-based approach via PickAtlas and SPM12. Results: Both healthy controls and PTSD patients showed widespread SC functional connectivity patterns with pre-motor and V1 cortical regions at rest. Notably, these SC connectivity patterns were stronger in controls. By contrast, virtually no PAG functional connectivity was observed in controls. However, PTSD patients further demonstrated extensive PAG functional connectivity with brain regions associated with emotional reactivity and defensive posturing (e.g., anterior insula, cingulum, pre/post central gyrus). Conclusions: These findings suggest that although the SC has extensive connections at rest in both controls and PTSD, the PAG may also be responsible for additional defensive posturing at rest. These findings emphasize the importance of identifying functional connectivity of the innate alarm system and related brain stem structures in PTSD. Supported By: Canadian Institutes of Health Research #137150 and #97914 Keywords: Functional MRI, Resting State, Posttraumatic Stress Disorder
... Restimulation of symptoms in PTSD patients also activated the cerebellar vermis (Pissiota, Frans, Fernandez, et al., 2002). Conversely, vermal lesions eliminated hyper-defensiveness, mouse killing, and freezing in rats (Supple, Cranney, Leaton, 1988). Vermal lesions also reduced anxiety but not fear in rats (Supple, Leaton, Fanselow,1987). ...
... 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.
... Notably, however, the cerebellum is often overlooked in models outlining the neural circuitry underlying fear-based responses to predators. Studies on rats with vermal cerebellar lesions reveal reduced unconditioned freezing responses in the presence of a cat, 3,26 where the vermis is thought to connect to the dlPAG via the fastigial nucleus and the SC, perhaps modulating activation of the dlPAG. ...
Article
The Lurcher mutant mice are characterized by massive cerebellar cortex degeneration. Besides their motor and cognitive disturbances, they exhibit both exaggerated blood corticosterone level surge and behavioral disinhibition when confronted to anxiogenic conditions (i.e. to a potential threat). In the present study, we assessed if such physiological and behavioral hyperactivity was also detectable in a fear-eliciting situation (actual threat). For this purpose, the behaviors and corticosterone level elevations in Lurcher mice were compared to those of littermate controls in the predator exposure test: mice were exposed either to a rat (exposure) or to a brief wave of the experimenter's hand (sham-exposure). While the basal corticosterone concentrations (24 H before testing) were not significantly different between mice of both genotypes, the post-exposure ones were higher in Lurcher than in control mice whatever the condition of the experimental design (exposure or sham-exposure). Predator exposure didn't provoke significant increase of corticosterone levels whatever the genotype. On the contrary, our data clearly showed that fear-related behaviors of cerebellar mutants facing a real threat were exacerbated in comparison to those of control mice. These results suggest that the cerebellar cortex not only participates to fear conditioning and anxiety but also actively contributes to the modulation of the innate fear-related behaviors.
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The behavioral effects were studied of monoclonal antibodies (MA) against A3G7 protein, which is known to be associated with the processes of nervous cell differentiation. Elaboration, storage, and retention of acoustic startle (ASR) habituation and freezing behavior were tested in adult rats. The MA applied in a dose of 50 ng on cerebellar vermis selectively impaired only the ASR long-term habituation storage whereas its dose of 5 mcg impaired both long-term habituation storage and fear-conditioned freezing. Application of 10 mcg of MA disrupted the elaboration and storage of the ASR short- and long-term habituation as well as fear-conditioned freezing. The results are considered as experimental verification of systemogenesis theory and hypothesis about a common molecular basis of learning and development.
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Studies were carried out into the effects of monoclonal antibodies to protein A3G7, which is associated with the differentiation of cerebellar and hippocampal neurons, on the development, retention, and reproduction of a habituated acoustic startle response and freezing behavior in rats. Application of monoclonal antibody (50 ng) to the vermis of the cerebellum selectively disrupted the retention of long-term habituation of the acoustic startle response, while a higher dose (5 micrograms) inhibited both retention of long-term habituation of the acoustic startle response and conditioned freezing behavior. Monoclonal antibody (10 micrograms) disrupted the development and retention of short-term and long-term extinction of the acoustic startle response, as well as conditioned freezing behavior. These data provide experimental support for the systemogenesis hypothesis of behavioral acts and for the concept that there is a single molecular basis for development and learning.
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Neonatal Borna disease virus (BDV) brain infection results in selective developmental damage to the hippocampal dentate gyrus and the cerebellum. When mature, neonatally BDV-infected rats show extreme locomotor hyperactivity and reduced freezing behavior in novel environments. Traditional interpretation of both of these behavioral abnormalities would suggest decreased anxiety in infected rats compared to normal animals. However, it also possible that the locomotor hyperactivity in infected rats reflects higher rather than reduced anxiety, and is the result of increased escape responses to aversive stimuli. The present experiments were undertaken to test a hypothesis about elevated anxiety in neonatally BDV-infected adult Lewis rats by studying their species-specific fear-related responses. Compared to normal subjects, BDV-infected rats exhibited locomotor hyperactivity and elevated defecation in a highly aversive, brightly lit open field. As expected, in a less aversive, dimly lit open field, uninfected controls increased ambulation, whereas infected rats significantly decreased locomotor activity and defecation. Unlike uninfected rats, BDV-infected rats exhibited an attenuated freezing response immediately after loud auditory stimuli. On the contrary, immediate freezing responses following footshock were comparable in the two groups of animals indicating an intact ability to freeze in BDV-infected rats. Despite a decreased baseline startle responsiveness, BDV-infected rats demonstrated increased sensitization of the startle response by preceding footshocks, suggesting a tendency toward elevated escape responses. Compared to normal subjects, BDV-infected rats showed decreased conditional freezing and elevated conditional defecation response in the context previously paired with aversive stimulation indicating sparing of an autonomic component of fear conditioning. The findings indicate that neonatally BDV-infected adult rats are hyperreactive to aversive stimuli, possibly as a result of chronic emotional abnormalities.
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Sudden changes in the sensory environment are frequently perceived as threats and may provoke defensive behavioral states. One such state is tonic immobility, a conserved defensive strategy characterized by a powerful suppression of movement and motor reflexes. Tonic immobility has been associated with multiple brainstem regions and cell types, but the underlying circuit is not known. Here, we demonstrate that a strong vibratory stimulus evokes tonic immobility in larval zebrafish defined by suppression of exploratory locomotion and sensorimotor responses. Using a circuit-breaking screen and targeted neuron ablations we show that cerebellar granule cells and a cluster of glutamatergic ventral prepontine neurons (vPPNs) that express key stress-associated neuropeptides are critical components of the circuit that suppresses movement. The complete sensorimotor circuit transmits information from primary sensory neurons through the cerebellum to vPPNs to regulate reticulospinal premotor neurons. These results show that cerebellar regulation of a neuropeptide-rich prepontine structure governs a conserved and ancestral defensive behavior that is triggered by inescapable threat.
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Anatomic studies of boys with attention-deficit/hyperactivity disorder (ADHD) have detected decreased volumes in total and frontal brain, basal ganglia, and cerebellar vermis. We tested these findings in a sample of girls with ADHD. Anatomic brain magnetic resonance images from 50 girls with ADHD, of severity comparable with that in previously studied boys, and 50 healthy female control subjects, aged 5 to 15 years, were obtained with a 1.5-T scanner with contiguous 2-mm coronal slices and 1.5-mm axial slices. We measured volumes of total cerebrum, frontal lobes, caudate nucleus, globus pallidus, cerebellum, and cerebellar vermis. Behavioral measures included structured psychiatric interviews, parent and teacher ratings, and the Wechsler vocabulary and block design subtests. Total brain volume was smaller in girls with ADHD than in control subjects (effect size, 0.40; P =.05). As in our previous study in boys with ADHD, girls with ADHD had significantly smaller volumes in the posterior-inferior cerebellar vermis (lobules VIII-X; effect size, 0.54; P =.04), even when adjusted for total cerebral volume and vocabulary score. Patients and controls did not differ in asymmetry in any region. Morphometric differences correlated significantly with several ratings of ADHD severity and were not predicted by past or present stimulant drug exposure. These results confirm previous findings for boys in the posterior-inferior lobules of the cerebellar vermis. The influence of the cerebellar vermis on prefrontal and striatal circuitry should be explored.
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To better understand learning mechanisms, one needs to study synaptic plasticity induced by behavioral training. Recently, it has been demonstrated that the cerebellum is involved in the consolidation of fear memory. Nevertheless, how the cerebellum contributes to emotional behavior is far from known. In cerebellar slices at 10 min and 24 hr following fear conditioning, we found a long-lasting potentiation of the synapse between parallel fibers and Purkinje cells in vermal lobules V-VI, but not in the climbing fiber synapses. The mechanism is postsynaptic, due to an increased AMPA response. In addition, in hotfoot mice with a primary deficiency of the parallel fiber to Purkinje cell synapse, cued (but not contextual) fear conditioning is affected. We propose that this synapse plays an important role in the learned fear and that its long-term potentiation may represent a contribution to the neural substrate of fear memory.
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Intricate anatomical connections exist between the cerebellar vermis and the hypothalamus. This study examined the effects of electrical microstimulation of the hypothalamus on Purkinje cell activity in the anterior cerebellar vermis (ACV) in the awake rabbit. Single-pulse stimulation of the hypothalamus evoked robust, short-latency modifications of Purkinje cell discharge. Heterogeneous response profiles were observed with cells demonstrating patterns of either unimodal excitation, biphasic excitation/inhibition or complex triphasic responses. These results support the hypothesis that the hypothalamus and ACV are functionally interactive, and may promote further understanding of the role of the ACV in emotional behavior and autonomic responses.
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In addition to coordinating movement, the cerebellum participates in motor learning, emotional behavior, and fear memory. Fear learning is reflected in a change of autonomic and somatic responses, such as heart rate and freezing, elicited by a neutral stimulus that has been previously paired with a painful one. Manipulation of the vermis affects these responses, and its reversible inactivation during the consolidation period 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. 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. In addition, in hotfoot mice, with a primary deficiency of parallel fiber to Purkinje cell synapse, short- and long-term fear memories are affected. 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.
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The effects of lesions of the cerebellar vermis on the acquisition of heart-rate conditioning in rats was examined. Lesions of the vermis severely attenuated the acquisition of conditioned bradycardic responses in a simple conditioning procedure in restrained rats. Importantly, the vermal lesions did not affect resting heart-rate, unconditioned heart-rate orienting responses to a tone stimulus or unconditioned heart-rate responses to the shock unconditioned stimulus. It is concluded that the cerebellar vermis is an essential component of a heart-rate conditioned response circuit in the rat. The similarities between these effects and those following manipulations of the amygdala are discussed.
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The effects of lesions of the cerebellum on the acquisition and retention of aversive Pavlovian conditioned bradycardia were examined in rabbits. Lesions of the anterior cerebellar vermis severely attenuated the acquisition of simple conditioned bradycardia without disrupting baseline heart rate (HR), or unconditioned HR responses. Also, lesions of the vermis performed after the acquisition of conditioned bradycardia eliminated evidence of prior conditioning. Bilateral lesions of the cerebellar hemispheres did not affect conditioned or unconditioned HR responses. These results were interpreted to indicate that anterior vermis lesions specifically disrupted part of an essential conditioned response pathway without interfering with the neural circuits that mediate unconditioned HR responding. These lesion data, coupled with recent electrophysiological evidence of learning-related changes in neuronal activity within the anterior vermis of the fear-conditioned rabbit, suggest that the anterior cerebellar vermis is critically involved in the acquisition and retention of this rapidly learned autonomic conditioned response.
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The anatomical connections between the midline cerebellum and the pontine parabrachial nucleus (PBN) were investigated in the rabbit using anterograde and retrograde axonal transport techniques. Small injections (20-50 nl) of cholera toxin conjugated to horseradish peroxidase (CT-HRP) or wheat germ agglutinin conjugated HRP (WGA-HRP) into the cortex of the anterior cerebellar vermis resulted in retrograde and anterograde-like label in the PBN. Focal injections of tracer into the PBN resulted in anterogradely labeled processes in the ACV and retrogradely labeled a small, but distinct group of Purkinje cells within the anterior vermis. Focal injections into the rostral fastigial nuclei (FN) resulted in anterograde-like label in the PBN, and PBN injections labeled FN neurons. Furthermore, the projection from the PBN to ACV is effective in driving cerebellar neurons as electrical microstimulation of the PBN evoked short-latency, phasic responses in ACV Purkinje cells. These experiments generated anatomical and physiological evidence for the existence of a neuroanatomical circuit connecting the midline cerebellum (ACV, FN) with the PBN, that may serve as a functional interface between the midline cerebellum and other brain stem nuclei with cardiovascular function, particularly with respect to the midline cerebellar role in classically conditioned cardiovascular responses.
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The present study has investigated the effects of electrical stimulation of the cerebellar posterior cortex in the conscious rabbit. Stimulation of lobule IX (the uvula) elicited an increase in mean arterial blood pressure and heart rate, accompanied by EEG desynchronization, pupillary dilatation and a specific motor reaction, consisting of pricking of the ears, neck stiffening and running movements. Stimulation of lobule VIII was ineffective in evoking equivalent responses. The administration of barbiturates reversed the cardiovascular response to uvula stimulation, producing a fall in mean arterial pressure. The characteristics of the pattern of responses obtained, together with the anatomical and electrophysical observations provided in the preceding paper (Bradley, Ghelarducci, La Noce, Paton, Spyer & Withington-Wray, 1990), suggest a possible involvement of uvula cortex in the expression of the alerting reaction in the rabbit.
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Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.
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Previous research has demonstrated that exposure to a cat produces a naltrexone-reversible antinociception as assessed in the formalin test in rats. Because different neurochemical mechanisms inhibit different forms of nociception, the present study examined whether presentation of a cat would also produce a naltrexone-reversible antinociception in the tail-flick response to radiant heat and electric shock. Exposure to the cat produced antinociception in both tail-flick paradigms. Naltrexone blocked the inhibition of the thermally evoked tail-flick response, but had no effect in the electric shock tail-flick paradigm. These results indicate that opioid mediation of stress-induced analgesia is determined, in part, by the nociceptive test employed.
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Innate defensive behaviors, such as freezing, are adaptive for avoiding predation. Freezing-related midbrain regions project to the cerebellum, which is known to regulate rapid sensorimotor integration, raising the question of cerebellar contributions to freezing. Here, we find that neurons of the mouse medial (fastigial) cerebellar nuclei (mCbN), which fire spontaneously with wide dynamic ranges, send glutamatergic projections to the ventrolateral periaqueductal gray (vlPAG), which contains diverse cell types. In freely moving mice, optogenetically stimulating glutamatergic vlPAG neurons that express Chx10 reliably induces freezing. In vlPAG slices, mCbN terminals excite ~20% of neurons positive for Chx10 or GAD2 and ~70% of dopaminergic TH-positive neurons. Stimulating either mCbN afferents or TH neurons augments IPSCs and suppresses EPSCs in Chx10 neurons by activating postsynaptic D2 receptors. The results suggest that mCbN activity regulates dopaminergic modulation of the vlPAG, favoring inhibition of Chx10 neurons. Suppression of cerebellar output may therefore facilitate freezing.
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The effects of electrical stimulation of the posterior cerebellar vermis in anaesthetized, decerebrate and conscious animals are described, and include marked changes in blood pressure and heart rate and an inhibition of the baroreceptor reflex. These effects appear to be restricted to lobule IX, and can be duplicated by chemical stimulation, indicating that they are a genuine cerebellar phenomenon. The results of both neuroanatomical and neurophysiological experiments to investigate the pathways responsible for the effects are described, and these show there to be a direct projection of Purkinje cell axons to the parabrachial nucleus. Experiments designed to test a possible involvement of lobule IX in the alerting response have proved negative, and while lobule IX itself appears to have no role in conditioned cardiovascular responses, lesions of lobules VI and VII do result in a significant impairment of the acquisition of conditioned bradycardia in the rabbit.
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The magnitude of classically conditioned bradycardia was studied in rabbits in which various cerebellar regions (lobule IX or the posterior vermis or the hemispheres) had been removed surgically. Lesions were shown histologically to be restricted to the cortex and the underlying white matter without any damage to the deep cerebellar nuclei. In the conditioning procedure, tones were employed as conditioned stimuli (CS) and ear shocks as unconditioned stimuli (US). Cerebellar lesions did not affect the characteristics of the bradycardic orienting response, baseline heart rate or the unconditioned tachycardic response to US. The conditioned bradycardia was significantly reduced in magnitude with respect to controls in rabbits submitted to removal of posterior vermis, while it was unaffected in lobule IX and hemispheric lesioned rabbits. The temporal pattern of development and habituation of the bradycardiac response through the conditioning session, as well as its topography, did not differ from controls in any of the lesioned rabbits. After the first conditioning session, some control rabbits were submitted to removal of the posterior vermis and then conditioned again, following an identical procedure. Their pre- and post-lesion conditioned responses did not exhibit any appreciable differences and were similar to the responses exhibited by a group of unoperated controls which were submitted to a reconditioning session. It is concluded that in the rabbit the cerebellar posterior vermis is involved in the initial acquisition of the classically conditioned bradycardia, but it is not the site of its memory trace.
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The effects of caspase inhibitors on different types of learning and memory were studied in adult rats on administration into the cerebral ventricles and application to the vermis of the cerebellum. The wide-spectrum caspase inhibitor z-VAD-fmk, given into the lateral ventricles of adult rats, facilitated the formation of long-term spatial memory in a water maze and increased the ability to rearrange the habit at the early stages of acquisition of this skill. Application of the specific caspase 3 inhibitor z-DEVD-CHO to the cerebellar vermis stimulated the extinction of an acoustic startle reaction but had no effect on its retention or reproduction. These results indicate that caspases may be involved in the mechanisms of learning and memory both via indirect influences on the linked processes of neurogenesis and apoptosis in the adult brain and by regulating synaptic efficiency.
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In this review results of human lesion studies are compared examining associative learning in the motor, emotional and cognitive domain. Motor and emotional learning were assessed using classical eyeblink and fear conditioning. Cerebellar patients were significantly impaired in acquisition of conditioned eyeblink and fear-related autonomic and skeletal responses. An additional finding was disordered timing of conditioned eyeblink responses. Cognitive learning was examined using stimulus-stimulus-response paradigms, with an experimental set-up closely related to classical conditioning paradigms. Cerebellar patients were impaired in the association of two visual stimuli, which could not be related to motor performance deficits. Human lesion and functional brain imaging studies in healthy subjects are in accordance with a functional compartmentalization of the cerebellum for different forms of associative learning. The medial zone appears to contribute to fear conditioning and the intermediate zone to eyeblink conditioning. The posterolateral hemispheres (that is lateral cerebellum) appear to be of additional importance in fear conditioning in humans. Future studies need to examine the reasonable assumption that the posterolateral cerebellum contributes also to higher cognitive forms of associative learning. Human cerebellar lesion studies provide evidence that the cerebellum is involved in motor, emotional and cognitive associative learning. Because of its simple and homogeneous micro-circuitry a common computation may underly cerebellar involvement in these different forms of associative learning. The overall task of the cerebellum may be the ability to provide correct predictions about the relationship between sensory stimuli.
Article
The cerebellar vermis is increasingly implicated in bipolar disorder (BD). In this study, we investigated vermis morphology in BD using a quantitative volumetric analysis. Volumes for total vermis and vermis subregions V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were calculated using high-resolution structural magnetic resonance imaging obtained from 44 individuals with BD (25 females and 19 males) and 43 healthy comparison (HC) subjects (26 females and 17 males). Total vermis volumes were compared between the BD and HC groups. Potential effects of vermis subregions and clinical features were explored. Total vermis volumes were significantly larger in the BD group than in the HC group (p = 0.02). There was a significant group-by-sex interaction (p = 0.02). Total vermis volumes were significantly larger in males with BD than HC males (p = 0.004); vermis volumes did not differ significantly between females with and without BD (p = 0.95). Subregion analyses showed a trend-level interaction between diagnosis and subregion (p = 0.07) in which subregion V1 volumes were significantly larger in BD participants (p = 0.001), with differences primarily driven by males (p = 0.001). Our findings demonstrate increases in cerebellar vermis volumes in males with BD. These findings support the presence of structural alterations in the cerebellar vermis in BD and furthermore the influence of sex on such changes.
Article
The present investigation sought to determine the neuroanatomical locus through which the amnesic and anxiolytic effects of the benzodiazepine agonist chlordiazepoxide are mediated. Rats were infused with either chlordiazepoxide (60 nmol/μl) or artificial CSF (1 μl) into either the frontal cortex, nucleus basalis magnocellularis/substantia innominata, amygdala, medial septum, hippocampus, or cerebellum and run in the open field to assess anxiety as thigmotaxia and in the Morris water maze to assess spatial learning. Other rats were given chlordiazepoxide (5 mg/kg) or saline (1 ml/kg) systemically and run in the open field and water maze. When chlordiazepoxide was administered systemically, rats showed significantly less thigmotaxia, but not overall activity, than controls in the open field, and were deficit in spatial learning, but not cue learning or swim speed, in the water maze. Intracranial infusions revealed a neuroanatomical specificity for the amnesic and anxiolytic actions of chlordiazepoxide. Infusions of chlordiazepoxide into the amygdala, but none of the other structures, reduced thigmotaxia without affecting overall activity levels whereas infusions into the medial septum, but none of the other structures, prevented spatial learning, but not cue learning, and reduced swim speed in the water maze. Together, these finding suggest that the medial septum and the amygdala mediate the amnesic and anxiolytic actions of chlordiazepoxide, respectively. Moreover, these results provide direct evidence that the amnesic and anxiolytic actions of chlordiazepoxide are independent.
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.
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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)
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
Evidence has accumulated which indicates that the hypothalamus may be concerned in certain elements of behavior the total pattern of which appears to be related to the outward manifestation of emotion. Stimulation of the hypothalamus in the region occupied by the medial bundle of the forebrain in the lateral part of the hypothalamus has been observed by Kabat and associates to cause mydriasis, increased respiration, struggling movements with clawing and biting, salivation, horripilation and sweating on the pads of the feet. In addition, cessation of peristalsis was noted, and sometimes evacuation of the bladder (Kabat, Anson, Magoun and Ranson¹; Kabat, Magoun and Ranson²; Ranson, Kabat and Magoun³; Kabat,⁴ and Kabat, Magoun and Ranson⁵). The points of stimulation were shown to be restricted largely to the lateral hypothalamic area. Similar results were obtained from anesthetized and unanesthetized cats. These reactions were not elicited when the infundibular
Article
Introduction Previous studies have shown that bilateral ablation of the amygdaloid nuclei and surrounding rhinencephalic structures in rodents, carnivores, and primates is uniquely characterized by a specific pattern of behavior. Animals sustaining such lesions exhibit behavior that is dominated by increased responsiveness to visual stimuli, hyperactivity, exaggerated oral activity, inability to recognize objects visually, loss of fear, and an increase in amount and diversity of sexual behavior.6,14-16,18-21,24Anatomical and electrophysiological studies of the amygdaloid nucleus and related structures have revealed efferent projections from the amygdala to widespread areas of the cortex and subcortex.1,8-11 More specifically, the ventromedial nucleus of the hypothalamus appears to be a strong recipient of fibers arising from the amygdaloid complex.Electrolytic lesions of the ventromedial nucleus in cats and rats2,12,23 have given rise to changes in behavior characterized by savage and aggressive attacks on other animals when approached, obesity, and hyposexual activity.In
Article
Results of 2 experiments indicate that an experimentally produced hyperreactivity facilitated initiation of mouse-killing in rats that did not previously develop any stable inhibition of interspecific aggression. Destruction of the corticomedial amygdala or interruption of the stria terminalis interfered with the development of such an inhibition on the basis of "social" influences, whereas lateral amygdaloid lesions had no effect on mouse-killing. (19 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Article
A preliminary attempt is made to analyze the intraspecific aggressive behavior of mammals in terms of specific neural circuitry. The results of stimulation, lesion, and recording studies of aggressive behavior in cats and rats are reviewed and analyzed in terms of three hypothetical motivational systems: offense, defense, and submission. A critical distinction, derived from ethological theory, is made between motivating stimuli that simultaneously activate functional groupings of motor patterning mechanisms, and releasing and directing stimuli that are necessary for the activation of discrete motor patterning mechanisms. It is suggested that motivating stimuli activate pathways that converge upon sets of homogeneous neurons, called motivational mechanisms, whose activity determines the motivational state of the animal. A defense motivational mechanism is hypothesized to be located in the midbrain central gray. In addition to tactile, auditory, and visual inputs from the paleospinothalamic tract, lateral lemniscus, and (perhaps) from the pretectum, it may receive inputs from a major forebrain pathway whose functional significance is not yet understood. A submission motivational mechanism is also thought to be located in the central gray. In addition to inputs for defense, it is thought to receive a necessary input from a “consociate (social familiarity cue) modulator” located in the ventromedial hypothalamus, which can switch behavior from defense to submission. The location of the hypothetical offense motivational mechanism is not known, although the pathways by which it is activated are traced in some detail. Brain mechanisms of aggression in primitive mammals and in primates are apparently similar to those in rats and cats.
Article
Small bilateral electrolytic lesions placed just posterior of the ventromedial hypothalamic nucleus cause a strong increase in offensive behavior. The histology suggests that damage to the ventral premammillary nucleus is responsible for this effect. A summary of the neuroanatomical literature shows that this structure is connected to most other brain structures reported to be involved in offensive behavior.
Article
Three lesion-induced rodent models of aggression were compared: septal, VMH (ventromedial hypothalamic) and O.B. (olfactory bulb). Significant similarities as well as differences emerged when different testing procedures were utilized to determine levels of aggressiveness. The results of this study suggest that much of the behavior observed in these aggressive models could be interpreted as being defensive in nature except for some instances of offensive display exhibited by the O.B. rats. The induction of muricidal behavior by lesioning and the duration of the other resultant aggressive syndromes were also explored.
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
Psychologists studying animal learning and motivation have recently been confronted with the importance of considering evolutionary function as part of the analysis of behavioral systems 1. This approach has fostered a better understanding of emotional or motivational states such as fear. Presently, when psychologists speak of fear they are referring to a motivational system that organizes an animal's responding at many different levels (e.g. overt behavior, autonomic functioning, etc.) so that it is co-ordinated toward the function of protecting the animal from environmental threats, more particularly, predation. Thus, fear can be considered as activation of a defensive motivational system2–4.
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
The effects of lesions of the cerebellar vermis on the acquisition of heart-rate conditioning in rats was examined. Lesions of the vermis severely attenuated the acquisition of conditioned bradycardic responses in a simple conditioning procedure in restrained rats. Importantly, the vermal lesions did not affect resting heart-rate, unconditioned heart-rate orienting responses to a tone stimulus or unconditioned heart-rate responses to the shock unconditioned stimulus. It is concluded that the cerebellar vermis is an essential component of a heart-rate conditioned response circuit in the rat. The similarities between these effects and those following manipulations of the amygdala are discussed.
Article
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.
Article
Lesions of the medial hypothalamus, medial accumbens, or septum were made in 21- to 25-day-old male hooded rats. Half of the animals in each group were subsequently reared in groups and the other half in isolation. When tested for defensiveness toward the experimenter at 31, 34, and 37 days postoperatively, rats with medial hypothalamic lesions were most hyperdefensive toward the experimenter if reared in isolation but were significantly more defensive than sham-lesioned animals even when reared in groups. Rats with septal lesions were significantly more defensive than sham-lesioned animals only when reared in isolation while rats with medial accumbens lesions were not different from controls whether reared individually or in groups. These results suggest that the medial hypothalamus may have a special importance in determining temperament since the hyperdefensiveness that results from interference with its functioning is resistant to experiential remediation.
Article
Unilateral electrolytic lesions of the fastigial nucleus of the cerebellum were made in six cats with a cauterizing current to a stereotaxically implanted electrode. Cats were perfused at days 6, 7, or 8 after this procedure, and their brains were serially sectioned at 300-μm intervals for staining by the Nauta-Gygax, Fink-Heimer procedure I, and cresylechtviolet methods. Lesions affected more than 80% of the fastigial nucleus in three cats and about 40% of the nucleus in one cat. The lesion did not involve the nucleus in two cats. Brains of the cats with the extensive lesions showed degenerating fibers into the hypothalamus, the central nuclei of the thalamus, and into several sites of the septal region, including nucleus accumbens septi, nucleus of the diagonal band (Broca), the dorsal anterior and medial septal nuclei, and more rostral into sites of the orbital gyri and into the gyrus rectus. Degenerating fibers to the more rostral sites traversed the internal capsule into the cingulum before coursing rostral ventrally. Although degeneration was noted bilaterally, ipsilateral degeneration was heavier at all sites. No ascending degenerating fibers were seen in the brains of the cats in which the nucleus was spared. Fink-Heimer preparations showed terminal degeneration in nuclei at the sites noted above. The rostral projections of the fastigial nucleus demonstrated by anatomic technics for the first time in this study correspond with those we previously demonstrated by electrically evoked potentials.
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
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
Since it is well established that cats rendered "savage" following bilateral lesions in the ventromedial hypothalamic nuclei manifest this type of behavior only when an external stimulus, e.g., tactile, auditory, or visual, is directed at them, a study was made of the degree to which some of the long ascending sensory systems participate in this phenomenon. After the hypothalamic lesions were made and the animals exhibited such adverse behavior, they were subjected to secondary bilateral lesions of the medial lemniscus and spinothalamic tracts in the lateral mesencephalic tegmentum. It was found that following destruction of these tracts (including part of the magnocellular division of the medial geniculate bodies) most animals no longer responded to external stimuli with the somatic and autonomic manifestations that characterize "rage," or that such responses were extremely altered and fragmentary.
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
The olfactory bulb, lateral septum, medial accumbens, medial hypothalamus, dorsal and median raphe, and amygdala are known from experiments in rats to participate in the inhibitory modulation of defensiveness and predation but not social aggression. The present paper surveys the influence of these structures in the inhibitory control of these same dimensions of agonistic behavior in other species. The existing evidence suggests that lesions in the lateral septum, medial accumbens, medial hypothalamus, or the dorsal and median raphe (or PCPA-induced depletion or serotonin) induce hyperreactivity to the experimenter in mice, rats, cats, dogs, and humans in every instance where they have been tested with one exception. The exception is that lesions in the medial hypothalamus of mice do not induce heightened reactivity. The same lesions do not cause this dramatic increase in reactivity to the experimenter in gerbils, hamsters, guinea pigs, or rabbits but do heighten some other species typical patterns of defensiveness such as alarm calls and avoidance of contact with conspecifics. Lesions in these same areas in monkeys have not been observed to heighten defensive behaviors. Predatory killing or killing of young conspecifics has been observed in hamsters, mice, rats, and cats in every instance where they have been examined following lesions of the olfactory bulbs, lateral septum, medial accumbens, medial hypothalamus, or the dorsal and median raphe nuclei (or PCPA-induced depletion of serotonin). Social aggression has been decreased with these same lesions in each case where they have been examined except for septal lesions in hamsters which have been reported to heighten social aggression. Across species, the consistency with which lesions of the olfactory region, lateral septum, medial accumbens, medial hypothalamus, and dorsal and median raphe nuclei alter defensiveness and predation but not social aggression supports the inference that neural systems exist which subserve the inhibitory modulation of these dimensions of behavior. Finally, the evidence that the disruption of functioning within these structures in humans results in increased agonistic responses to environmental stimuli serves to further establish the important role of this neural circuitry in the normal inhibitory modulation of agonistic behavior in humans.
Article
The classically conditioned nictitating membrane response (NMR) of the rabbit is useful for analyses of brain structures and pathways involved in mammalian associative learning. Lesions of the entire cerebellum, its nuclei or its efferent pathway abolish conditioned NMR learning and prevent its reacquisition. Until now it has not been clear whether the cerebellar cortex is an essential part of the circuitry for NMR conditioning. Here we report that small lesions of the cerebellar cortex in the hemispheral portion of lobule VI, with sparing of the underlying nuclei, abolish the ipsilateral conditioned NMR and prevent it from being reacquired.
Article
Classical conditioning of the eyelid response in the rabbit was used to investigate the neuronal structures mediating basic associative learning of discrete, adaptive responses. Lesions of the ipsilateral dentate-interpositus nuclei, but not of the cerebellar cortex, abolished the learned eyeblink response. Recordings from these nuclei have revealed neuronal responses related to the learning of the response. Stimulating these recording sites produced the eyelid response. The dentate-interpositus nuclei were concluded to be critically involved in the learning and production of classically conditioned responses.
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
Following restricted lesions to the septal region of the forebrain, rats developed significant increases in emotional reactivity and in startle response. Previously acquired conditioned emotional responses were diminished, but there was no evidence of decrement in the rate of acquisition of new conditioned emotional responses. The extent of the changes in emotional behavior seemed to be "roughly commensurate with the extent of injury to the fornix column, suggesting the possible importance of this complex paleocortical fiber bundle in the transmission of neural impulses involved in determining affective behavior."
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Involvement of amygdala in inhibitory control over aggression in the rat: A synopsis
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Cerebellum: Essential for classical conditioning of the eyeblink response
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Cerebellar projections to the Papez circuit
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