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Serotonergic Modulation of Orientation Tuning of Neurons in Primary Visual Cortex of Anesthetized Mice
Abstract
Introduction: Sensory processing is profoundly regulated by brain neuromodulatory systems. One of the main neuromodulators is serotonin which influences higher cognitive functions such as different aspects of perceptual processing. So, malfunction in the serotonergic system may lead to visual illusion in psychiatric disorders such as autism and schizophrenia. In this work, we examined the serotonergic modulation of visual responses of neurons to stimulus orientation in the primary visual cortex. Methods: Eight-weeks old naive mice were anesthetized and craniotomy was done on the region of interest in primary visual cortex. Spontaneous and visual-evoked activities of neurons were recorded before and during the electrical stimulation of dorsal raphe nucleus using in vivo whole-cell patch-clamp recording. Square-wave grating of 12 orientations was presented. Data was analyzed and Wilcoxon signed-rank test, used in order to compare the data of two conditions that belong to the same neurons, with or without electrical stimulation. Results: The serotonergic system changed orientation tuning of about 60 % recorded neurons by decreasing the mean firing rate in two independent visual response components: gain and baseline response. It also increased mean firing rate in a small number of neurons (about 20%). Beyond that, it left the preferred orientation and sensitivity of neurons unchanged. Conclusion: However, serotonergic modulation showed a bi-directional effect; it seems to cause predominately divisive and subtractive decreases in the visual responses of the neurons in the primary visual cortex that can modify the balance between internal and external sensory signals and result in disorders.
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Controlling gain of cortical activity is essential to modulate weights between internal ongoing communication and external sensory drive. Here, we show that serotonergic input has separable suppressive effects on the gain of ongoing and evoked visual activity. We combined optogenetic stimulation of the dorsal raphe nucleus (DRN) with wide-field calcium imaging, extracellular recordings, and iontophoresis of serotonin (5-HT) receptor antagonists in the mouse visual cortex. 5-HT1A receptors promote divisive suppression of spontaneous activity, while 5-HT2A receptors act divisively on visual response gain and largely account for normalization of population responses over a range of visual contrasts in awake and anesthetized states. Thus, 5-HT input provides balanced but distinct suppressive effects on ongoing and evoked activity components across neuronal populations. Imbalanced 5-HT1A/2A activation, either through receptor-specific drug intake, genetically predisposed irregular 5-HT receptor density, or change in sensory bombardment may enhance internal broadcasts and reduce sensory drive and vice versa.
Sensory perception arises from the integration of externally and internally driven representations of the world. Disrupted balance of these representations can lead to perceptual deficits and hallucinations. The serotonin-2A receptor (5-HT2AR) is associated with such perceptual alterations, both in its role in schizophrenia and in the action of hallucinogenic drugs. Despite this powerful influence on perception, relatively little is known about how serotonergic hallucinogens influence sensory processing in the neocortex. Using widefield and two-photon calcium imaging and single-unit electrophysiology in awake mice, we find that administration of the hallucinogenic selective 5-HT2AR agonist DOI (2,5-dimethoxy-4-iodoamphetamine) leads to a net reduction in visual response amplitude and surround suppression in primary visual cortex, as well as disrupted temporal dynamics. However, basic retinotopic organization, tuning properties, and receptive field structure remain intact. Our results provide support for models of hallucinations in which reduced bottom-up sensory drive is a key factor leading to altered perception.
A lot of efforts have been made to understand the structure and function of neocortical circuits. In fact, a promising way to understand the functions of cortical circuits is the classification of the neural types, based on their different properties. Recent studies focused on applying modern computational methods to classify neurons based on molecular, morphological, physiological, or mixed of these criteria. Although there are studies in the literature on in vitro/vivo extracellular or in vitro intracellular recordings, a study on the classification of neuronal types using in vivo whole-cell patch-clamp recordings is still lacking. We thus proposed a novel semi-supervised classification method based on waveform shape of neurons' spikes using in vivo whole-cell patch-clamp recordings. We, first, detected spike candidates. Then discriminative features were extracted from the time samples of the spikes using discrete cosine transform. We then extracted the center of clusters using fuzzy c-mean clustering and finally, the neurons were classified using the minimum distance classifier. We distinguished three types of neurons: excitatory pyramidal cells (Pyr) and two types of inhibitory neurons: GABAergic- parvalbumin positive (PV), and somatostatin positive (SST) non-pyramidal cells in layer II/III of the mice primary visual cortex. We used 10-fold cross validation in our study. The classification accuracy for PV, Pyr, and SST was 91.59 ± 1.69, 97.47 ± 0.67, and 89.06 ± 1.99, respectively. Overall, the algorithm correctly classified 92.67 ± 0.54% of the cells, confirming the relative robustness of the discriminant functions. The performance of the method was further assessed on in vitro recordings by using a pool of 50 neurons from Allen institute Cell Types Database (5 major subtypes of neurons: Pyr, PV, SST, 5HT3a, and vasoactive intestinal peptide (VIP) cells). Its overall accuracy was 84.13 ± 0.81% on this data set using cross validation framework. The proposed algorithm is thus a promising new tool in recognizing cell's type with high accuracy in laboratories using in vivo/vitro whole-cell patch-clamp recording technique. The developed programs and the entire dataset are available online to interested readers.
All neuronal circuits are subject to neuromodulation. Modulatory effects on neuronal processing and resulting behavioral changes are most commonly reported for higher order cognitive brain functions. Comparatively little is known about how neuromodulators shape processing in sensory brain areas that provide the signals for downstream regions to operate on. In this article, we review the current knowledge about how the monoamine neuromodulators serotonin, dopamine and noradrenaline influence the representation of sensory stimuli in the mammalian sensory system. We review the functional organization of the monoaminergic brainstem neuromodulatory systems in relation to their role for sensory processing and summarize recent neurophysiological evidence showing that monoamines have diverse effects on early sensory processing, including changes in gain and in the precision of neuronal responses to sensory inputs. We also highlight the substantial evidence for complementarity between these neuromodulatory systems with different patterns of innervation across brain areas and cortical layers as well as distinct neuromodulatory actions. Studying the effects of neuromodulators at various target sites is a crucial step in the development of a mechanistic understanding of neuronal information processing in the healthy brain and in the generation and maintenance of mental diseases.
Serotonin, an important neuromodulator in the brain, is implicated in affective and cognitive functions. However, its role even for basic cortical processes is controversial. For example, in the mammalian primary visual cortex (V1), heterogenous serotonergic modulation has been observed in anesthetized animals. Here, we combined extracellular single-unit recordings with iontophoresis in awake animals. Weexamined the role of serotonin on well-defined tuning properties (orientation, spatial frequency, contrast, and size) in V1 of two male macaque monkeys. We find that in the awake macaque the modulatory effect of serotonin is surprisingly uniform: it causes a mainly multiplicative decrease of the visual responses and a slight increase in the stimulus-selective response latency. Moreover, serotonin neither systematically changes the selectivity or variability of the response, nor the interneuronal correlation unexplained by the stimulus (“noise-correlation”). The modulation by serotonin has qualitative similarities with that for a decrease in stimulus contrast, but differs quantitatively from decreasing contrast. It can be captured by a simple additive change to a threshold-linear spiking nonlinearity. Together, our results show that serotonin is well suited to control the response gain of neurons in V1 depending on the animal’s behavioral or motivational context, complementing other known state-dependent gain-control mechanisms.
Neural circuits in the cerebral cortex consist primarily of excitatory pyramidal (Pyr) cells and inhibitory interneurons. Interneurons are divided into several subtypes, in which the two major groups are those expressing parvalbumin (PV) or somatostatin (SOM). These subtypes of interneurons are reported to play distinct roles in tuning and/or gain of visual response of pyramidal cells in the visual cortex. It remains unclear whether there is any quantitative and functional difference between the PV → Pyr and SOM → Pyr connections. We compared unitary inhibitory postsynaptic currents (uIPSCs) evoked by electrophysiological activation of single presynaptic interneurons with population IPSCs evoked by photo-activation of a mass of interneurons in vivo and in vitro in transgenic mice in which PV or SOM neurons expressed channelrhodopsin-2, and found that at least about 14 PV neurons made strong connections with a postsynaptic Pyr cell while a much larger number of SOM neurons made weak connections. Activation or suppression of single PV neurons modified visual responses of postsynaptic Pyr cells in 6 of 7 pairs whereas that of single SOM neurons showed no significant modification in 8 of 11 pairs, suggesting that PV neurons can act solo whereas most of SOM neurons may act in chorus on Pyr cells.
How the processing of signals carried by sensory neurons supports perceptual decisions is a long-standing question in neuroscience. The ability to record neuronal activity in awake animals while they perform psychophysical tasks near threshold has been a key advance in studying these questions. Trial-to-trial correlations between the activity of sensory neurons and the decisions reported by animals ('choice probabilities'), even when measured across repeated presentations of an identical stimulus provide insights into this problem. But understanding the sources of such co-variability between sensory neurons and behavior has proven more difficult than it initially appeared. Below, we discuss our current understanding of what gives rise to these correlations.
Serotoninergic innervation of the central nervous system is provided by hindbrain raphe nuclei (B1–B9). The extent to which each raphe subdivision has distinct topographic organization of their projections is still unclear. We provide a comprehensive description of the main targets of the rostral serotonin (5-HT) raphe subgroups (B5–B9) in the mouse brain. Adeno-associated viruses that conditionally express GFP under the control of the 5-HT transporter promoter were used to label small groups of 5-HT neurons in the dorsal (B7d), ventral (B7v), lateral (B7l), and caudal (B6) subcomponents of the dorsal raphe (DR) nucleus as well as in the rostral and caudal parts of the median raphe (MR) nucleus (B8 and B5, respectively), and in the supralemniscal (B9) cell group. We illustrate the distinctive and largely non-overlapping projection areas of these cell groups: for instance, DR (B7) projects to basal parts of the forebrain, such as the amygdala, whereas MR (B8) is the main 5-HT source to the hippocampus, septum, and mesopontine tegmental nuclei. Distinct subsets of B7 have preferential brain targets: B7v is the main source of 5-HT for the cortex and amygdala while B7d innervates the hypothalamus. We reveal for the first time the target areas of the B9 cell group, demonstrating projections to the caudate, prefrontal cortex, substantia nigra, locus coeruleus and to the raphe cell groups. The broad topographic organization of the different raphe subnuclei is likely to underlie the different functional roles in which 5-HT has been implicated in the brain. The present mapping study could serve as the basis for genetically driven specific targeting of the different subcomponents of the mouse raphe system.
In frontalized mammals it has been demonstrated that adaptation produces shift of the peak of the orientation tuning curve of neuron following frequent or lengthier presentation of a non-preferred stimulus. Depending on the duration of adaptation the shift is attractive (toward the adapter) or repulsive (away from the adapter). Mouse exhibits a salt-and-pepper cortical organization of orientation maps, hence this species may respond differently to adaptation. To examine this question, we determined the effect of twelve minutes of adaptation to one particular orientation on neuronal orientation tuning curves in V1 of anesthetized mice. Multi-unit activity of neurons in V1 was recorded in a conventional fashion. Cells were stimulated with sine-wave drifting gratings whose orientation tilted in steps. Results revealed that similarly to cats and monkeys, majority of cells shifted their optimal orientation in the direction of the adapter while a small proportion exhibited a repulsive shift. Moreover, initially untuned cells showing poor tuning curves reacted to adaptation by displaying sharp orientation selectivity. It seems that modification of the cellular property following adaptation is a general phenomenon observed in all mammals in spite of the different organization pattern of the visual cortex. This study is of pertinence to comprehend the mechanistic pathways of brain plasticity.
The brain continuously adapts its processing machinery to behavioural demands. To achieve this, it rapidly modulates the operating mode of cortical circuits, controlling the way that information is transformed and routed. This article will focus on two experimental approaches by which the control of cortical information processing has been investigated: the study of state-dependent cortical processing in rodents and attention in the primate visual system. Both processes involve a modulation of low-frequency activity fluctuations and spiking correlation, and are mediated by common receptor systems. We suggest that selective attention involves processes that are similar to state change, and that operate at a local columnar level to enhance the representation of otherwise non-salient features while suppressing internally generated activity patterns.
Serotonin (5-hydroxytryptamine [5-HT]) is known to influence a wide range of behaviors and physiological processes, but relatively little is known about events that trigger 5-HT release. To address this issue, we recorded from neurons in the dorsal raphe nucleus (DRN) in rats performing an odor-guided spatial decision task. A large fraction of DRN neurons showed transient firing time locked to behavioral events on timescales as little as 20 ms. DRN transients were sometimes correlated with reward parameters, but also encoded specific sensorimotor events, including stimulus identity and response direction. These behavioral correlates were diverse but showed no apparent relationship with waveform or other firing properties indicative of neurochemical identity. These results suggest that the 5-HT system does not encode a unitary signal and that it will broadcast specific information to the forebrain with speed and precision sufficient not only to modulate but also to dynamically sculpt ongoing information processing.
Synaptic inhibition plays an important role in shaping receptive field (RF) properties in the visual cortex. However, the underlying mechanisms remain not well understood, partly because of difficulties in systematically studying functional properties of cortical inhibitory neurons in vivo. Here, we established two-photon imaging guided cell-attached recordings from genetically labeled inhibitory neurons and nearby "shadowed" excitatory neurons in the primary visual cortex of adult mice. Our results revealed that in layer 2/3, the majority of excitatory neurons exhibited both On and Off spike subfields, with their spatial arrangement varying from being completely segregated to overlapped. In contrast, most layer 4 excitatory neurons exhibited only one discernable subfield. Interestingly, no RF structure with significantly segregated On and Off subfields was observed for layer 2/3 inhibitory neurons of either the fast-spike or regular-spike type. They predominantly possessed overlapped On and Off subfields with a significantly larger size than the excitatory neurons and exhibited much weaker orientation tuning. These results from the mouse visual cortex suggest that different from the push-pull model proposed for simple cells, layer 2/3 simple-type neurons with segregated spike On and Off subfields likely receive spatially overlapped inhibitory On and Off inputs. We propose that the phase-insensitive inhibition can enhance the spatial distinctiveness of On and Off subfields through a gain control mechanism.
Fundamental brain functions depend on a balance between excitation (E) and inhibition (I) that is highly adjusted to a 20-80% set point in layer 5 pyramidal neurons (L5PNs) of rat visual cortex. Dysregulations of both the E-I balance and the serotonergic system in neocortical networks lead to serious neuronal diseases including depression, schizophrenia, and epilepsy. However, no link between the activation of neuronal 5-hydroxytryptamine receptors (5-HTRs) and the cortical E-I balance has yet been reported. Here we used a combination of patch-clamp recordings of composite stimulus-locked responses in L5PN following local electrical stimulations in either layer 2/3 or 6, simultaneous measurement of excitatory and inhibitory conductance dynamics, together with selective pharmacological targeting and single-cell reverse transcriptase-polymerase chain reaction. We show that cortical serotonin shifts the E-I balance in favor of more E and we reveal fine and differential modulations of the E-I balance between 5-HTR subtypes, in relation to whether layer 2/3 or 6 was stimulated and in concordance with the specific expression pattern of these subtypes in pyramidal cells and deep interneurons. This first evidence for the functional segregation of 5-HTR subtypes sheds new light on their coherent functioning in polysynaptic sensory circuits.
To study the molecular mechanism how cortical areas are specialized in adult primates, we searched for area-specific genes in macaque monkeys and found striking enrichment of serotonin (5-hydroxytryptamine, 5-HT) 1B receptor mRNA, and to a lesser extent, of 5-HT2A receptor mRNA, in the primary visual area (V1). In situ hybridization analyses revealed that both mRNA species were highly concentrated in the geniculorecipient layers IVA and IVC, where they were coexpressed in the same neurons. Monocular inactivation by tetrodotoxin injection resulted in a strong and rapid (<3 h) downregulation of these mRNAs, suggesting the retinal activity dependency of their expression. Consistent with the high expression level in V1, clear modulatory effects of 5-HT1B and 5-HT2A receptor agonists on the responses of V1 neurons were observed in in vivo electrophysiological experiments. The modulatory effect of the 5-HT1B agonist was dependent on the firing rate of the recorded neurons: The effect tended to be facilitative for neurons with a high firing rate, and suppressive for those with a low firing rate. The 5-HT2A agonist showed opposite effects. These results suggest that this serotonergic system controls the visual response in V1 for optimization of information processing toward the incoming visual inputs.
The modulation of K+ channels by serotonin (5-HT) receptors was studied by coinjecting Xenopus oocytes with mRNA transcribed in vitro from a cloned 5-HT 1C subtype (5-HT1C) receptor gene, together with size-fractionated mRNA isolated from rat cerebral cortex that expresses K+ channels. After intracellular loading with EGTA to block Ca2(+)-dependent chloride currents, these oocytes responded to 5-HT with an inward current associated with a decrease in membrane conductance. Membrane current responses were small or absent in oocytes injected with either mRNA alone. We conclude that 5-HT1C receptors are able to cause the closing of a class of K+ channels expressed by cortex mRNA in a Ca2(+)-independent manner. The coupling between the receptors and channels appears to be mediated by the inositol phospholipid second messenger pathway, since activation of this pathway by application of serum evoked a similar closing current.
Zusammenfassung Histochemische und pharmakologische Experimente sprechen stark dafür, dass Dopamin, Noradrenalin und 5-Hydroxitryptamin im Hirnstamm der Ratte in drei Typen von Nervenzellen und Endsynapsen gespeichert werden.
We have studied 5-hydroxytryptamine (5-HT) release in the hippocampal formation following electrical stimulation of the dorsal and median raphé nuclei in the behaving rat. The primary finding in this study is a decrease in neuronal release of serotonin in the dorsal hippocampal formation following electrical stimulation of either the dorsal or median raphé nucleus in conscious rats. At no time did electrical stimulation of either raphé nucleus result in behavioral, including vigilance state, changes. The amount of 5-HT released was found to be frequency dependent with higher frequencies (20 Hz) producing larger decreases in release of 5-HT. However, the pattern of release differs between the two raphé nuclei. Extracellular levels of 5-HT decrease during stimulation of the dorsal raphé, whereas levels decrease only following cessation of stimulation of the median raphé nucleus. This may relate to the patterns of innervation of the dorsal hippocampal formation by these two midbrain raphé nuclei and also may reflect an inhibition of median raphé cell firing during stimulation of the dorsal raphé. Electrical stimulation of the dorsal raphé in anesthetized animals resulted in an enhanced release of 5-HT. The suppression of 5-HT release in the dorsal hippocampal formation in behaving animals was long-lasting (over 2 h), suggesting that the control mechanisms that regulate 5-HT release operate over a long time-course. This difference in release between non-anesthetized and anesthetized animals may relate to anesthesia blocking long- and/or short-loop serotonin recurrent axonal collaterals negatively feeding back onto 5-HT1A and 5-HT1D somatodendritic autoreceptors on raphé neurons. Further, the anesthetized animal has diminished monoaminergic "gating" influences on the hippocampal formation, whereas the behaving animal is more complex with behavioral (vigilance) states associated with different patterns of gating of information flow through the hippocampal formation.
Neocortical neurons expressing the serotonin 5-HT3 receptor (5-HT3R) were characterized in rat acute slices by using patch-clamp recordings combined with single-cell RT-PCR and histochemical labeling. The 5-HT3A receptor subunit was expressed selectively in a subset of GABAergic interneurons coexpressing cholecystokinin (CCK) and vasoactive intestinal peptide (VIP). The 5-HT3B subunit was never detected, indicating that 5-HT3Rs expressed by neocortical interneurons did not contain this subunit. In 5-HT3A-expressing VIP/CCK interneurons, serotonin induced fast membrane potential depolarizations by activating an inward current that was blocked by the selective 5-HT3R antagonist tropisetron. Furthermore, we observed close appositions between serotonergic fibers and the dendrites and somata of 5-HT3R-expressing neurons, suggestive of possible synaptic contacts. Indeed, in interneurons exhibiting rapid excitation by serotonin, local electrical stimulations evoked fast EPSCs of large amplitude that were blocked by tropisetron. Finally, 5-HT3R-expressing neurons were also excited by a nicotinic agonist, indicating that serotonergic and cholinergic fast synaptic transmission could converge onto VIP/CCK interneurons. Our results establish a clear correlation between the presence of the 5-HT3A receptor subunit in neocortical VIP/CCK GABAergic interneurons, its functional expression, and its synaptic activation by serotonergic afferent fibers from the brainstem raphe nuclei.
The synaptic mechanisms of feature coding in the visual cortex are poorly understood, particularly in awake animals. The ratio between excitation (E) and inhibition (I) might be constant across stimulus space, controlling only the gain and timing of neuronal responses, or it might change, directly contributing to feature coding. Whole-cell recordings in L2/3 of awake mice revealed that the E/I ratio systematically declines with increasing stimulus contrast or size. Suppressing somatostatin (SOM) neurons enhanced the E and I underlying size tuning, explaining SOM neurons’ role in surround suppression. These data imply that contrast and size tuning result from a combination of a changing E/I ratio and the tuning of total synaptic input. Furthermore, they provide experimental support in awake animals for the “Stabilized Supralinear Network,” a model that explains diverse cortical phenomena, and suggest that a decreasing E/I ratio with increasing cortical drive could contribute to many different cortical computations.
Monoaminergic Modulation of Cortical Excitability serves as an integrative and comprehensive comparison of the diverse and complex modulatory action of dopamine, noradrenaline, and serotonin receptors in the cortex. The volume is organized into several sections offering a broad spectrum of opinions on how the monoamine systems affect cortical function from a cellular/sub-cellular level to a system level. The complexity of these interactions are discussed in light of recent data showing how disruption of these systems dramatically affects the memory formation and information processing in the cortex. © 2007 Springer Science+Business Media, LLC. All rights reserved.
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Serotonin (5-hydroxytriptamine; 5-HT) is implicated in a variety of brain functions including not only the regulation of mood and control of behavior but also the modulation of perception. 5-HT neurons in the dorsal raphe nucleus (DRN) often fire locked to sensory stimuli, but little is known about how 5-HT affects sensory processing, especially on this timescale. Here, we used an optogenetic approach to study the effect of 5-HT on single-unit activity in the mouse primary olfactory (anterior piriform) cortex. We show that activation of DRN 5-HT neurons rapidly inhibits the spontaneous firing of olfactory cortical neurons, acting in a divisive manner, but entirely spares sensory-driven firing. These results identify a new role for serotonergic modulation in dynamically regulating the balance between different sources of neural activity in sensory systems, suggesting a possible role for 5-HT in perceptual inference.
Significance statement:
Serotonin is implicated in a wide variety of (pato)physiological functions including perception, but its precise role has remained elusive. Here, using optogenetic tools in vivo, we show that serotonergic neuromodulation prominently inhibits the spontaneous electrical activity of neurons in the primary olfactory cortex on a rapid (<1 s) timescale but leaves sensory responses unaffected. These results identify a new role for serotonergic modulation in rapidly changing the balance between different sources of neural activity in sensory systems.
Experience shapes the central nervous system throughout life. Structural and functional plasticity confers a remarkable ability on the brain, allowing neural circuits to adequately adapt to dynamic environments. This process can require selective adjustment of many excitatory and inhibitory synapses in an organized manner, in such a way as to enhance representations of behaviorally important sensory stimuli while preserving overall network excitability. The rules and mechanisms that orchestrated these changes across different synapses and throughout neuronal ensembles are beginning to be understood. Here, we review the evidence connecting synaptic plasticity to functional plasticity and perceptual learning, focusing on the roles of various neuromodulatory systems in enabling plasticity of adult neural circuits. However, the challenge remains to appropriately leverage these systems and forms of plasticity to persistently improve perceptual abilities and behavioral performance.
Re-entrant or feedback pathways between cortical areas carry rich and varied information about behavioural context, including attention, expectation, perceptual tasks, working memory and motor commands. Neurons receiving such inputs effectively function as adaptive processors that are able to assume different functional states according to the task being executed. Recent data suggest that the selection of particular inputs, representing different components of an association field, enable neurons to take on different functional roles. In this Review, we discuss the various top-down influences exerted on the visual cortical pathways and highlight the dynamic nature of the receptive field, which allows neurons to carry information that is relevant to the current perceptual demands.
Serotonin (5-HT) shapes brain networks during development and modulates a wide spectrum of essential neuronal functions ranging from perception and cognitive appraisal to emotional responses in the mature brain. Deficits in 5-HT-moderated synaptic signaling fundamentally impact the pathophysiology and long-term outcome of neurodevelopmental disorders. Our understanding of how 5-HT-dependent modulation of circuit configuration influences social cognition and emotional learning has been enhanced by recent insight into the molecular and cellular mechanisms of synapse formation and plasticity. In this review, we discuss emerging concepts as to how defects in synaptic plasticity impact our biosocial brain and how recent findings regarding 5-HT's role in brain development and function provide insight into the cellular and physiological basis of neurodevelopmental disorders.
Brain circuits process information through specialized neuronal subclasses interacting within a network. Revealing their interplay requires activating specific cells while monitoring others in a functioning circuit. Here we use a new platform for two-way light-based circuit interrogation in visual cortex in vivo to show the computational implications of modulating different subclasses of inhibitory neurons during sensory processing. We find that soma-targeting, parvalbumin-expressing (PV) neurons principally divide responses but preserve stimulus selectivity, whereas dendrite-targeting, somatostatin-expressing (SOM) neurons principally subtract from excitatory responses and sharpen selectivity. Visualized in vivo cell-attached recordings show that division by PV neurons alters response gain, whereas subtraction by SOM neurons shifts response levels. Finally, stimulating identified neurons while scanning many target cells reveals that single PV and SOM neurons functionally impact only specific subsets of neurons in their projection fields. These findings provide direct evidence that inhibitory neuronal subclasses have distinct and complementary roles in cortical computations.
The median (MR) and dorsal raphe (DR) nuclei contain the majority of the 5-hydroxytryptamine (5-HT, serotonin) neurons that project to limbic forebrain regions, are important in regulating homeostatic functions and are implicated in the etiology and treatment of mood disorders and schizophrenia. The primary synaptic inputs within and to the raphe are glutamatergic and GABAergic. The DR is divided into three subfields, i.e., ventromedial (vmDR), lateral wings (lwDR) and dorsomedial (dmDR). Our previous work shows that cell characteristics of 5-HT neurons and the magnitude of the 5-HT(1A) and 5-HT(1B) receptor-mediated responses in the vmDR and MR are not the same. We extend these observations to examine the electrophysiological properties across all four raphe subfields in both 5-HT and non-5-HT neurons. The neurochemical topography of glutamatergic and GABAergic cell bodies and nerve terminals were identified using immunohistochemistry and the morphology of the 5-HT neurons was measured. Although 5-HT neurons possessed similar physiological properties, important differences existed between subfields. Non-5-HT neurons were indistinguishable from 5-HT neurons. GABA neurons were distributed throughout the raphe, usually in areas devoid of 5-HT neurons. Although GABAergic synaptic innervation was dense throughout the raphe (immunohistochemical analysis of the GABA transporters GAT1 and GAT3), their distributions differed. Glutamate neurons, as defined by vGlut3 anti-bodies, were intermixed and co-localized with 5-HT neurons within all raphe subfields. Finally, the dendritic arbor of the 5-HT neurons was distinct between subfields. Previous studies regard 5-HT neurons as a homogenous population. Our data support a model of the raphe as an area composed of functionally distinct subpopulations of 5-HT and non-5-HT neurons, in part delineated by subfield. Understanding the interaction of the cell properties of the neurons in concert with their morphology, local distribution of GABA and glutamate neurons and their synaptic input, reveals a more complicated and heterogeneous raphe. These results provide an important foundation for understanding how specific subfields modulate behavior and for defining which aspects of the circuitry are altered during the etiology of psychological disorders.
5-HT(4) receptors control brain physiological functions such as learning and memory, feeding and mood behaviour as well as gastro-intestinal transit. 5-HT(4) receptors are one of the 5-HT receptors for which the available drugs and signalling knowledge are the most advanced. Several therapeutic 5-HT(4) receptor drugs have been commercialized. Therefore, the hope that 5-HT(4) receptors could also be the target for brain diseases is reasonable. Several major devastating illnesses could benefit from 5-HT(4) receptors-directed therapy such as Alzheimer's disease, feeding-associated diseases such as anorexia and major depressive disorders.
The brain maintains internal models of its environment to interpret sensory inputs and to prepare actions. Although behavioral
studies have demonstrated that these internal models are optimally adapted to the statistics of the environment, the neural
underpinning of this adaptation is unknown. Using a Bayesian model of sensory cortical processing, we related stimulus-evoked
and spontaneous neural activities to inferences and prior expectations in an internal model and predicted that they should
match if the model is statistically optimal. To test this prediction, we analyzed visual cortical activity of awake ferrets
during development. Similarity between spontaneous and evoked activities increased with age and was specific to responses
evoked by natural scenes. This demonstrates the progressive adaptation of internal models to the statistics of natural stimuli
at the neural level.
Human perception has recently been characterized as statistical inference based on noisy and ambiguous sensory inputs. Moreover, suitable neural representations of uncertainty have been identified that could underlie such probabilistic computations. In this review, we argue that learning an internal model of the sensory environment is another key aspect of the same statistical inference procedure and thus perception and learning need to be treated jointly. We review evidence for statistically optimal learning in humans and animals, and re-evaluate possible neural representations of uncertainty based on their potential to support statistically optimal learning. We propose that spontaneous activity can have a functional role in such representations leading to a new, sampling-based, framework of how the cortex represents information and uncertainty.
G protein-coupled receptors (GPCRs) are key transmembrane recognition molecules for regulatory signals such as light, odors, taste hormones, and neurotransmitters. In addition to activating guanine nucleotide binding proteins (G proteins), GPCRs associate with a variety of GPCR-interacting proteins (GIPs). GIPs contain structural interacting domains that allow the formation of large functional complexes involved in G protein-dependent and -independent signaling. At the cellular level, other functions of GIPs include targeting of GPCRs to subcellular compartments and their trafficking to and from the plasma membrane. Recently, roles of GPCR-GIP interactions in central nervous system physiology and pathologies have been revealed. Here, we highlight the role of GIPs in some important neurological and psychiatric disorders, as well as their potential for the future development of therapeutic drugs.
Centrifugal serotonergic fibers innervate the olfactory bulb, but the importance of these projections for olfactory processing is unclear. We examined serotonergic modulation of sensory input to olfactory glomeruli using mice that express synaptopHluorin in olfactory receptor neurons (ORN). Odor-evoked synaptic input to glomeruli was attenuated by increased serotonin signaling through serotonin 2C (5-HT2C) receptors and amplified by decreased serotonergic activity. Intravital multiphoton calcium imaging revealed that 5-HT2C receptor activation amplified odor-evoked activity in a subset of juxtaglomerular cells and attenuated glutamate release from ORN terminals via GABA(B) receptors. Endogenous serotonin released by electrical stimulation of the dorsal raphe nucleus attenuated odor-evoked responses without detectable bias in glomerular position or odor identity. Weaker glomerular responses, however, were less sensitive to raphe stimulation than strong responses. Our data indicate that the serotonergic system regulates odor inputs in the olfactory bulb and suggest that behavioral states may alter odor processing at the earliest stages.
The predominant effect of dopamine, norepinephrine and serotonin on the photically-evoked urinary activity was a prolonged inhibition of firing. These amines were also able to block acetylcholine-induced excitations and for longer periods of time than GABA.
The activation of different subtypes of the 5-HT1 receptor can be associated with specific behavioral responses. The present review discusses different categories of behavioral studies that have examined functional distinctions among 5-HT1 receptors. These include: 1) behavioral responses elicited by selective 5-HT receptor agonists; 2) drug discrimination experiments; 3) studies of sensorimotor reactivity and motivated behavior; and 4) behavioral models of clinical psychotherapeutic effects.
The serotoninergic innervation of the marmoset (New World monkey, Callithrix jacchus) cerebral cortex has been analyzed by using immunocytochemistry. The use of a sensitive monoclonal antibody against serotonin allowed the visualization of the fine morphology of individual axons. Two types of terminal axons were demonstrated: one has sparse, small, ovoid varicosities (dia. less than 1 μm), and the other has large, spheroidal varicosities (up to 5 μm in dia.), which are more densely clustered. The first type of axon is distributed through all cortical layers, with a characteristic laminar distribution that varies from area to area. The second type of axons was distributed sparsely in all regions but was markedly denser in the frontal and anterior parietal lobes, and in the hippocampal formation.
Axons with large varicosities typically surrounded certain cell bodies and proximal dendrites, forming pericellular arrays, or baskets. These morphological specializations were most frequent in the frontal and anterior parietal cortex, where they were found around stellate and horizontal cells in layer I and around stellate and bipolar cells in layer II and III. Similar baskets were also found in the hippocampal formation, mainly along the border between the hilus and the granule cell layer of the dentate gyrus, across the CA4 field, and at each side of the pyramidal cell layer of the CA3 regions. The distribution and cellular morphology of the cell surrounded by the 5-HT basket fibres were suggestive of a subpopulation of interneurons, possibly GABAergic and/or peptidergic. In agreement with previous reports on the innervation of the cerebral cortex of other mammalian species, the marmoset cerebral cortex is innervated by two separate subsystems of serotoninergic axons. One of these may have a strong and specific influence on the cortical inhibitory circuitry, via relay through cortical interneurons.
The present study was conducted to examine the actions of norepinephrine (NE) and serotonin (5-HT) on the multiphasic, visually evoked discharges of cells recorded from the visual cortex (area 17) of anesthetized Long-Evans pigmented rats. Visual responses of 51 cells, evoked by computer controlled presentation of moving visual stimuli, were examined before, during and after low level microiontophoretic application of NE (1-55 nA) or 5-HT (1-50 nA). Drug-induced changes in stimulus-evoked and spontaneous discharges were quantitatively assessed by computer analysis of peri-event histograms. In the majority of cases tested, NE produced a net enhancement of visually evoked responses by facilitating excitatory and inhibitory components of stimulus-bound discharges. By contrast, 5-HT tended to suppress stimulus-evoked excitation and inhibition in many cases to the extent that neurons were no longer responsive to appropriate visual stimuli. In selected cases we were able to demonstrate additional effects of NE and 5-HT on response threshold, direction selectivity and discrimination of receptive field borders. For example, in some cells NE was capable of revealing evoked responses to visual stimuli which were previously ineffective in eliciting stimulus-bound discharges. In other instances, changes in cell activity evoked by stimulus movement across the visual field were accentuated during NE application in such a way that unit discharges at receptive field borders were more sharply defined in comparison to control conditions. 5-HT, on the other hand, was capable of decreasing the contrast between spontaneous and visually evoked discharge at receptive field boundaries. In summary, these results suggest that endogenously released NE and 5-HT may modulate, by complimentary actions, the magnitude of responses of visual cortical neurons to afferent synaptic inputs. Moreover, these monoaminergic projection systems may also have the capacity to modify the threshold of detection of afferent signals within a neuronal network as well as alter feature extraction properties of the circuit.
Data gathered for the past 30 years suggest 5-HT abnormalities in depression, but it is still unknown whether serotonin has a major causal role. Depression is often regarded as a result of defective serotonergic function, but it is also possible that this defect is an indication of an ineffective compensatory response to abnormally high serotonergic function. Abnormal 5-HT function could be a result of disturbances at various pre- and postsynaptic levels. The disturbances reported at most of these levels are largely subject to dispute. Specific abnormalities can occur in specific subgroups and can be either state or trait dependent. Nevertheless, 5-HT hypotheses have been helpful for the development of drugs, although even here there is disagreement as to their actual mechanism of action. Two recent developments can help to clear up these uncertainties. First, the discovery of many types of 5-HT receptors and the increasing availability of drugs specifically related to them provides new adaptable research tools as well as the possibility of new therapies. Second, data provided by studies of humans and by animal models suggest that vulnerability to depression depends on disturbances of both 5-HT and the hypothalamohypophysial axis.
The pattern of activity and excitability of cortical neurons and neuronal circuits is dependent upon the interaction between glutamatergic and GABAergic fast-activating transmitter systems as well as the state of the more slowly acting transmitters such as ACh, norepinephrine, 5-HT, and histamine. Through the activation of GABAA receptors, GABAergic neurons regulate the amplitude and duration of EPSPs and, in so doing, control the level of functional activation of NMDA receptors. In contrast, activation of muscarinic, adrenergic, serotoninergic, histaminergic, and glutamate metabotropic receptors controls the excitability and pattern of action potential generation in identified pyramidal cells through increases or decreases in various K+ conductances. Activation of muscarinic, alpha 1-adrenergic, or glutamate metabotropic receptors on layer V burst-generating corticotectal or corticopontine neurons results in depolarization through a reduction in a K+ conductance and a switch in the firing mode from repetitive burst firing to single-spike activity. In contrast, activation of muscarinic, beta-adrenergic, H2-histaminergic, and serotoninergic receptors on regular-spiking layer II/III, V, and/or VI corticogeniculate pyramidal cells results in a decrease in spike frequency adaptation and increased responsiveness to depolarizing inputs through a reduction in a slow Ca(2+)-activated K+ current IAHP, and/or a voltage-dependent K+ current, IM. Through these, and other, mechanisms the spatial and temporal pattern of activity generated in cortical circuits is regulated by both intracortical and extracortical neurotransmitter systems.
Cholinergic and serotonergic fiber systems invade the developing visual cortex several weeks before eye opening; both transmitters have been implicated in plasticity of neocortical circuits. These transmitters have been presumed to act predominantly through second messenger-coupled receptors, because fast cholinergic or serotonergic neurotransmission has never been observed in neocortex. However, acetylcholine and serotonin also act on ligand-gated ion channels; the nicotinic acetylcholine receptor and the serotonin 5-HT3 receptor, respectively. Here, using whole-cell patch-clamp techniques in developing ferret visual cortex, we pharmacologically isolated fast, spontaneous, and evoked cholinergic and serotonergic synaptic events in pyramidal cells and interneurons of all cortical layers. The number of cells receiving such inputs increased with the ingrowth of thalamic afferents, and the frequencies of the spontaneous events increased at eye opening. Thus, both acetylcholine and serotonin can mediate fast synaptic transmission in the visual cortex; the early onset of these mechanisms suggests a role during initial stages of circuit formation and during subsequent experience-dependent remodeling of cortical connections.
Serotonergic projections are widespread in the developing neocortex, but their functions are obscure. The effects of 5-HT3 receptor agonists on cortical circuit response properties were studied in slices of ferret primary visual cortex using high-speed optical imaging of voltage-sensitive dye signals and whole-cell patch-clamp recording. Activation of the 5-HT3 receptor decreased the amplitude and lateral extent of excitation throughout postnatal development. This effect peaks after eye opening, which indicates a function for serotonergic modulation of circuit responses during the period of refinement of cortical connections. Whole-cell patch-clamp recordings from single neurons revealed that synaptic responses evoked by white matter stimulation were reduced by 5-HT3 receptor agonists, whereas the frequency of spontaneous GABAergic synaptic currents was enhanced dramatically. This indicates that the modulation of spontaneous synaptic activity by fast-acting serotonin receptors is reflected in an inhibition of the circuit response, in line with the notion of background synaptic activity altering the spatiotemporal integration properties of cortical cells by changing their membrane potential and their electrotonic structure. These mechanisms may regulate the response properties of intrinsic circuits in both the adult and developing neocortex.
The diverse array of behavioral effects of serotonin form the basis for understanding its potential role as an etiological marker in psychiatric disorders and for the successful pharmacologic intervention of drugs regulating serotonin neurotransmission in behavior. General theories of the behavioral functions of serotonin have implicated serotonin as a general inhibitor of behavioral responding and in modulating motor behavior. The ability of serotonin to regulate behavioral satiety and macronutrient selection provides the basis for pharmacologic treatment of obesity and eating disorders. The role of serotonin in behavioral suppression may be important in social behavior involving aggression and anxiety. The role of serotonin in neuroendocrine regulation provides a basis for understanding serotonin dysregulation in depression. Animal behavior tests are being used to better understand the neural substrates underlying the behavioral effects of antidepressant drugs and to address important issues in clinical treatment. The integration of information between basic and clinical studies provides the basis for future development of more sophisticated pharmacologic treatments of psychiatric disorders.
Cortical neuromodulatory transmitter systems refer to those classical neurotransmitters such as acetylcholine and monoamines, which share a number of common features. For instance, their centers are located in subcortical regions and send long projection axons to innervate the cortex. The same transmitter can either excite or inhibit cortical neurons depending on the composition of postsynaptic transmitter receptor subtypes. The overall functions of these transmitters are believed to serve as chemical bases of arousal, attention and motivation. The anatomy and physiology of neuromodulatory transmitter systems and their innervations in the cerebral cortex have been well characterized. In addition, ample evidence is available indicating that neuromodulatory transmitters also play roles in development and plasticity of the cortex. In this article, the anatomical organization and physiological function of each of the following neuromodulatory transmitters, acetylcholine, noradrenaline, serotonin, dopamine, and histamine, in the cortex will be described. The involvement of these transmitters in cortical plasticity will then be discussed. Available data suggest that neuromodulatory transmitters can modulate the excitability of cortical neurons, enhance the signal-to-noise ratio of cortical responses, and modify the threshold for activity-dependent synaptic modifications. Synaptic transmissions of these neuromodulatory transmitters are mediated via numerous subtype receptors, which are linked to multiple signal transduction mechanisms. Among the neuromodulatory transmitter receptor subtypes, cholinergic M(1), noradrenergic beta(1) and serotonergic 5-HT(2C) receptors appear to be more important than other receptor subtypes for cortical plasticity. In general, the contribution of neuromodulatory transmitter systems to cortical plasticity may be made through a facilitation of NMDA receptor-gated processes.
The effects of serotonin (5-HT) on excitability of two cortical interneuronal subtypes, fast-spiking (FS) and low threshold spike (LTS) cells, and on spontaneous inhibitory postsynaptic currents (sIPSCs) in layer V pyramidal cells were studied in rat visual cortical slices using whole-cell recording techniques. Twenty-two of 28 FS and 26 of 35 LTS interneurons responded to local application of 5-HT. In the group of responsive neurons, 5-HT elicited an inward current in 50% of FS cells and 15% of LTS cells, an outward current was evoked in 41% of FS cells and 81% of LTS cells, and an inward current followed by an outward current in 9% of FS cells and 4% LTS cells. The inward and outward currents were blocked by a 5-HT(3) receptor antagonist, tropisetron, and a 5-HT(1A) receptor antagonist, NAN-190, respectively. The 5-HT-induced inward and outward currents were both associated with an increase in membrane conductance. The estimated reversal potential was more positive than -40 mV for the inward current and close to the calculated K(+) equilibrium potential for the outward current. The 5-HT application caused an increase, a decrease, or an increase followed by a decrease in the frequency of sIPSCs in pyramidal cells. The 5-HT(3) receptor agonist 1-(m-chlorophenyl) biguanide increased the frequency of larger and fast-rising sIPSCs, whereas the 5-HT(1A) receptor agonist (+/-)8-hydroxydipropylaminotetralin hydrobromide elicited opposite effects and decreased the frequency of large events. These data indicate that serotonergic activation imposes complex actions on cortical inhibitory networks, which may lead to changes in cortical information processing.
Acetylcholine is involved in a variety of brain functions. In the visual cortex, the pattern of cholinergic innervation varies considerably across different mammalian species and across different cortical layers within the same species. The physiological effects of acetylcholine in the visual cortex display complex responses, which are likely due to cholinergic receptor subtype composition in cytoplasm membrane as well as interaction with other transmitter systems within the local neural circuitry. The functional role of acetylcholine in visual cortex is believed to improve the signal-to-noise ratio of cortical neurons during visual information processing. Available evidence suggests that acetylcholine is also involved in experience-dependent visual cortex plasticity. At the level of synaptic transmission, activation of muscarinic receptors has been shown to play a permissive role in visual cortex plasticity. Among the muscarinic receptor subtypes, the M(1) receptor seems to make a predominant contribution towards modifications of neural circuitry. The signal transduction cascade of the cholinergic pathway may act synergistically with that of the NMDA receptor pathway, whose activation is a prerequisite for cortical plasticity.
The serotonin system and NMDA receptors (NMDARs) in prefrontal cortex (PFC) are both critically involved in the regulation of cognition and emotion under normal and pathological conditions; however, the interactions between them are essentially unknown. Here we show that serotonin, by activating 5-HT(1A) receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT(1A) receptors. This effect of 5-HT(1A) receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) abolished the 5-HT(1A) modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT(1A) activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT(1A) activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesin-based dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways. The 5-HT(1A)-NMDAR interaction provides a potential mechanism underlying the role of serotonin in controlling emotional and cognitive processes subserved by PFC.
Historically, the locus coeruleus-norepinephrine (LC-NE) system has been implicated in arousal, but recent findings suggest that this system plays a more complex and specific role in the control of behavior than investigators previously thought. We review neurophysiological, anatomical, and modeling studies in monkey that support a new theory of LC-NE function. LC neurons exhibit two modes of activity, phasic and tonic. Phasic LC activation is driven by the outcome of task-related decision processes and is proposed to facilitate ensuing behaviors and to help optimize task performance. When utility in the task wanes, LC neurons exhibit a tonic activity mode, associated with disengagement from the current task and a search for alternative behaviors. Monkey LC receives prominent, direct inputs from the anterior cingulate (ACC) and orbitofrontal cortices (OFC), both of which are thought to monitor task-related utility. We propose that these prefrontal areas produce the above patterns of LC activity to optimize the utility of performance on both short and long time scales.
The dorsal raphe nucleus (DRN)-serotonin (5-HT) system has been implicated in acute responses to stress and stress-related psychiatric disorders such as anxiety and depression. Stress alters serotonin (5-HT) release in a regionally specific manner. For example, swim stress increases extracellular levels of 5-HT in the striatum and decreases levels in the lateral septum. This finding suggests that the 5-HT efferents to the striatum and lateral septum arise from distinct populations of DRN neurons that are differentially affected by swim stress. To further examine this, retrograde axonal transport of fluorescent RetroBeads was used to identify the distribution of DRN neurons projecting to the lateral septum and striatum in the rat brain. Retrograde labeling from the lateral septum was observed primarily within the more caudal portions of the DRN, while labeling from the striatum was observed in neurons located in the more rostral regions of the DRN. Few cell bodies were observed that were labeled from both the striatum and lateral septum suggesting that DRN neurons do not send collateralized projections to the septal region and striatum. Many septal- and striatal-projecting neurons in the DRN exhibited 5-HT, and collateralized projections, when observed, were immunoreactive for 5-HT. Taken together with previous microdialysis studies, these results support the existence of distinct DRN-5-HT-forebrain projections that are differentially regulated by stress.
Cortical processing is strongly influenced by the actions of neuromodulators such as acetylcholine (ACh). Early studies in anaesthetized cats argued that acetylcholine can cause a sharpening of orientation tuning functions and an improvement of the signal-to-noise ratio (SNR) of neuronal responses in primary visual cortex (V1). Recent in vitro studies have demonstrated that acetylcholine reduces the efficacy of feedback and intracortical connections via the activation of muscarinic receptors, and increases the efficacy of feed-forward connections via the activation of nicotinic receptors. If orientation tuning is mediated or enhanced by intracortical connections, high levels of acetylcholine should diminish orientation tuning. Here we investigate the effects of acetylcholine on orientation tuning and neuronal responsiveness in anaesthetized marmoset monkeys. We found that acetylcholine caused a broadening of the orientation tuning in the majority of cells, while tuning functions became sharper in only a minority of cells. Moreover, acetylcholine generally facilitated neuronal responses, but neither improved signal-to-noise ratio, nor reduced trial-to-trial firing rate variance systematically. Acetylcholine did however, reduce variability of spike occurrences within spike trains. We discuss these findings in the context of dynamic control of feed-forward and lateral/feedback connectivity by acetylcholine.