926 research outputs found
Cholinergic Control of Cortical Circuit Activity
Cholinergic neurons of the basal forebrain send extensive projections to all regions of the neocortex and are critically involved in a diverse array of cognitive functions, including sensation, attention and learning. Cholinergic signaling also plays a crucial role in the moment-to-moment control of ongoing cortical state transitions that occur during periods of wakefulness. Yet, the underlying circuit mechanisms of synaptic cholinergic function in the neocortex remain unclear. Moreover, acetylcholine continues to be widely viewed as a slow and diffuse neuromodulator, despite the preponderance of in vivo evidence demonstrating rapid cholinergic function. In this study, we used a combination of optogenetics and in vitro electrophysiology to examine spatiotemporally precise control of cortical network activity by endogenous acetylcholine. We show that even brief activation of cholinergic afferents could powerfully suppress evoked cortical recurrent activity for several seconds. This suppression was reliant on the engagement of both nicotinic and muscarinic acetylcholine receptors. Nicotinic receptors mediated transient suppression by acting in the superficial cortical layers, while muscarinic receptors mediated prolonged suppression in layer 4. In agreement, we found nicotinic-mediated excitation of inhibitory neurons in the supragranular layers, and muscarinic-mediated hyperpolarization of excitatory cells in layer 4. Together, these findings present novel circuit mechanisms for fast and robust cholinergic signaling in neocortex
Connectivity, plasticity, and function of neuronal circuits in the zebrafish olfactory forebrain
For most living animals such as worms, insects, fishes, rodents and humans, chemical cues from the environment (odorants) play critical roles in guiding behaviors important for survival, including preying, mating, breeding, and escaping. How those odorants are detected, identified, learned, remembered, and used by the nervous system is a longstanding interest for neuroscientists. An animal that is well-suited to study the processing of odor information at the level of neuronal circuits is the zebrafish (Danio rerio) because its small brain size allows for exhaustive quantitative measurements of neuronal activity patterns.
In vertebrates, odorants are detected by olfactory sensory neurons in the nose and transmitted to the first olfactory processing center in the brain, the olfactory bulb
(OB), as patterns of neuronal activities. In the OB, neuronal activity patterns from the nose are transformed into odor-specific spatiotemporal activity patterns across second order neurons, the mitral cells. These discrete neuronal activity patterns are broadcast to various target areas. The largest of these higher brain areas is piriform cortex or its teleost homolog, the posterior zone of dorsal telencephalon (Dp). In this higher brain region, an odor-encoding neuronal activity pattern from the OB is thought to be encoded as a "gestalt", or "odor object", and possibly stored in memory by specific modifications of functional connections between distributed neuronal ensembles. Such neuronal ensembles are also thought to be connected with other brain regions that involved in the control of different behaviors. Therefore, by inducing a specific activity pattern in the OB, which then retrieves related neuronal ensemble activities in a higher brain region, an odor cue (or even partial cue) recalls an odor object memory that may further trigger a specific set of behavioral responses in the animal.
The mechanisms by which odor object memory is synthesized, stored, and recalled is of major interest in neuroscience because it may provide fundamental insights into associative memory functions. However, dissecting higher brain functions such as associative memory will first require basic understanding of connectivity, plasticity, and related modulating factors for the underlying neuronal circuits. In this inaugural dissertation, I present an approach to study the connectivity, plasticity, and cholinergic modulation of the neural circuits in Dp and present new insights into the synaptic organizations of this neuronal network.
In results part one, I show that transgenes can be introduced directly into the adult zebrafish brain by herpes simplex type I viruses (HSV-1) or electroporation. I developed a new procedure to target electroporation to defined brain areas, e.g. Dp, and identified promoters that produced strong long-term expression. These new methods fill an important gap in the spectrum of molecular tools for zebrafish and are likely to have a wide range of applications. In results part two, I used a combination of electroporation, optogenetics, electrophysiology, and pharmacology to study the intrinsic connectivity and plasticity in neural circuits of Dp. I found that connectivity between any pair of excitatory neurons in Dp is extremely sparse (connection probability < 1.5 %). The connection probability of inhibitory synapses is also sparse but slightly higher (< 2.5 %). Furthermore, I found that connectivity can be functionally modified by activity-dependent synaptic plasticity including spike timing-dependent long-term potentiation. Moreover, I show that cholinergic agonists differentially modulate excitatory and inhibitory synaptic transmissions in Dp, consistent with the notion that cholinergic neuromodulation controls experience-dependent changes in functional connectivity. These findings show that the synaptic organization of Dp is similar to mammalian piriform cortex and provide quantitative insights into the functional organization of a brain area that is likely to be involved in associative memory
Experience-driven formation of parts-based representations in a model of layered visual memory
Growing neuropsychological and neurophysiological evidence suggests that the
visual cortex uses parts-based representations to encode, store and retrieve
relevant objects. In such a scheme, objects are represented as a set of
spatially distributed local features, or parts, arranged in stereotypical
fashion. To encode the local appearance and to represent the relations between
the constituent parts, there has to be an appropriate memory structure formed
by previous experience with visual objects. Here, we propose a model how a
hierarchical memory structure supporting efficient storage and rapid recall of
parts-based representations can be established by an experience-driven process
of self-organization. The process is based on the collaboration of slow
bidirectional synaptic plasticity and homeostatic unit activity regulation,
both running at the top of fast activity dynamics with winner-take-all
character modulated by an oscillatory rhythm. These neural mechanisms lay down
the basis for cooperation and competition between the distributed units and
their synaptic connections. Choosing human face recognition as a test task, we
show that, under the condition of open-ended, unsupervised incremental
learning, the system is able to form memory traces for individual faces in a
parts-based fashion. On a lower memory layer the synaptic structure is
developed to represent local facial features and their interrelations, while
the identities of different persons are captured explicitly on a higher layer.
An additional property of the resulting representations is the sparseness of
both the activity during the recall and the synaptic patterns comprising the
memory traces.Comment: 34 pages, 12 Figures, 1 Table, published in Frontiers in
Computational Neuroscience (Special Issue on Complex Systems Science and
Brain Dynamics),
http://www.frontiersin.org/neuroscience/computationalneuroscience/paper/10.3389/neuro.10/015.2009
Cholinergic modulation of auditory and prefrontal cortical interactions
Much of the previous work investigating the influence of cholinergic tone on cortical circuits has emphasized global states of arousal and local circuit dynamics; however the cholinergic system is well-suited to coordinate large-scale cortical interactions due to its diffuse cortically projecting arborization and diverse influence on the various cell types within the cortical microcircuit. In this thesis I examined the function of cortical cholinergic tone in supporting long-range cortical interactions, feed-forward sensory signaling, and active processing of behaviorally relevant stimuli. I utilized optogenetic stimulation and silencing of the cholinergic nucleus basalis while recording from the auditory-prefrontal cortical circuit as well as performing local drug infusions in awake mice. I demonstrate that prefrontal cortex actively responds to cortico-cortical sensory input in animals passively presented with acoustic stimuli and that muscarinic receptor binding within auditory cortex is essential for feedforward pathways from auditory cortex to transmit sensory related neural signals. Specifically, muscarinic antagonists applied to the auditory cortex disrupt sensory signaling within auditory cortex as well as bottom up signaling to prefrontal cortex. Furthermore, muscarinic antagonists attenuated the influence of cortical cholinergic release on recording channels closest to drug infusion, confirming the efficacy of muscarinic antagonism, and demonstrating that aspects of cholinergic modulation are locally generated within cortical circuits, while others are globally generated in large networks. In task performing animals, I observed that optogenetic silencing of cholinergic nucleus basalis neurons attenuates the magnitude of prefrontal cortex alpha power following correct behavioral choice and that alpha in prefrontal and auditory cortical local field potentials are actively involved in behavioral learning during extinction, suggesting that cholinergic tone is involved in maintaining and updating the value of stimuli across behavioral trials. In summary, my thesis supports a model where endogenous cholinergic signaling is an essential component of normal auditory processing during low attentive states, contributes to circuit activation through local and large network mechanisms, and supports essential cortical dynamics that contribute to active behavioral processing of stimuli
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Functional Consequences of Dendritic Inhibition in the Hippocampus
The ability to store and recall memories is an essential function of nervous systems, and at the core of subjective human experience. As such, neuropsychiatric conditions that impair our memory capacity are devastating. Learning and memory in mammals have long been known to depend on the hippocampus, which has motivated widespread research efforts that converge on two broad themes: determining how different cell types in the hippocampus interact to generate neural activity patterns (structure), and determining how neural activity patterns implement learning and memory (function). Central to both these pursuits are pyramidal cells (PCs) in CA1, the primary hippocampal output, which transform excitatory synaptic inputs into the action potential output patterns that encode information about locations or events relevant for memory. CA1 PCs are embedded in a network of diverse inhibitory (GABA-releasing) interneurons, which may play unique roles in sculpting the activity patterns of PCs that implement memory functions. As a consequence, investigating the functional impact of defined GABAergic interneurons can provide an experimental entry point for linking neural circuit structure to defined computations and behavioral functions in the hippocampal memory system. In this thesis I have applied a panel of novel methodologies to the mouse hippocampus in vitro and in vivo to link structure to function and behavior, and determine 1) how hippocampal inhibitory cell types shape distinct patterns of PC activity, and 2) how these inhibitory cell types contribute to the encoding of contextual fear memories.
To first establish the means by which interneuron subtypes contribute to PC activity patterns, I used optogenetic techniques to activate spatiotemporally distributed synaptic excitation to CA1 in vitro, and recorded from PCs to quantify the frequency of output spikes relative to input levels. I subsequently used a dual viral and transgenic approach to combine this technique with selective pharmacogenetic inactivation of identified interneurons during synaptic excitation. I found that inactivating somatostatin-expressing (Som+) dendrite-targeting interneurons increased the gain of PC input-output transformations by causing more output spikes, while inactivating parvalbumin-expressing (Pvalb+) soma-targeting interneurons did not. Inactivating Som+ inhibitory interneurons allowed the dendrites of PCs to generate local NMDA receptor-mediated electrogenesis in response to synaptic input, resulting in high frequency bursts of output spikes. This discovery suggests neuronal coding via hippocampal burst spiking output can be regulated by Som+ dendrite-targeting interneurons in CA1.
Specific types of neural codes are believed to have different functional roles. Neural coding with burst spikes is known to support hippocampal contributions to classical contextual fear conditioning (CFC). In CFC the hippocampus encodes the multisensory context as a conditioned stimulus (CS), whose burst spiking output is paired with the aversive unconditioned stimulus (US) in the amygdala, allowing for fear memory recall upon future exposure to the CS. To investigate the contribution of Som+ interneurons to this behavior, I designed a CFC task for head-fixed mice, allowing for optical recording and manipulation of activity in defined CA1 cell types during learning. Pharmacogenetic inactivation of CA1 Som+ interneurons, but not Pvalb+ interneurons, prevented the encoding of CFC. 2-photon Ca2+ imaging revealed that during CFC the US activated CA1 Som+ interneurons via cholinergic input from the medial septum, driving inhibition to the PC distal dendrites that receive coincident excitatory input from the entorhinal cortex. Inactivating Som+ interneurons increases PC population activity, and suppressing dendritic inhibition during the US alone is sufficient to prevent fear learning. These results suggest sensory features of the US reach CA1 PCs through entorhinal inputs, and thus require active inhibitory filtering by Som+ interneurons to ensure hippocampal output exclusively encodes the CS during CFC.
In conclusion, I found that Som+ interneurons in CA1 are an effective regulator of PC burst spiking because they inhibit dendritic electrogenesis. This function is used by the hippocampus to prevent the US from influencing the burst spike output of PCs that encode the CS, ensuring successful CFC. This work bridges the gap between cells, circuits, and behavior, and provides mechanistic insight into one of our most essential cognitive functions - the ability to learn and remember
Incessant transitions between active and silent states in cortico-thalamic circuits and altered neuronal excitability lead to epilepsy
La ligne directrice de nos expĂ©riences a Ă©tĂ© l'hypothĂšse que l'apparition et/ou la persistance des fluctuations de longue durĂ©e entre les Ă©tats silencieux et actifs dans les rĂ©seaux nĂ©ocorticaux et une excitabilitĂ© neuronale modifiĂ©e sont les facteurs principaux de l'Ă©pileptogenĂšse, menant aux crises dâĂ©pilepsie avec expression comportementale. Nous avons testĂ© cette hypothĂšse dans deux modĂšles expĂ©rimentaux diffĂ©rents. La dĂ©affĂ©rentation corticale chronique a essayĂ© de rĂ©pliquer la dĂ©affĂ©rentation physiologique du neocortex observĂ©e pendant le sommeil Ă ondes lentes. Dans ces conditions, caractĂ©risĂ©es par une diminution de la pression synaptique et par une incidence augmentĂ©e de pĂ©riodes silencieuses dans le systĂšme cortico-thalamique, le processus de plasticitĂ© homĂ©ostatique augmente lâexcitabilitĂ© neuronale. Par consĂ©quent, le cortex a oscillĂ© entre des pĂ©riodes actives et silencieuses et, Ă©galement, a dĂ©veloppĂ© des activitĂ©s hyper-synchrones, s'Ă©tendant de lâhyperexcitabilitĂ© cellulaire Ă l'Ă©pileptogenĂšse focale et Ă des crises Ă©pileptiques gĂ©nĂ©ralisĂ©es. Le modĂšle de stimulation sous-liminale chronique (« kindling ») du cortex cĂ©rĂ©bral a Ă©tĂ© employĂ© afin d'imposer au rĂ©seau cortical une charge synaptique supĂ©rieure Ă celle existante pendant les Ă©tats actifs naturels - Ă©tat de veille ou sommeil paradoxal (REM). Dans ces conditions un mĂ©canisme diffĂ©rent de plasticitĂ© qui sâest exprimĂ© dans le systĂšme thalamo-corticale a imposĂ© pour des longues pĂ©riodes de temps des oscillations continuelles entre les Ă©poques actives et silencieuses, que nous avons appelĂ©es des activitĂ©s paroxysmiques persistantes. IndĂ©pendamment du mĂ©canisme sous-jacent de l'Ă©pileptogenĂšse les crises dâĂ©pilepsie ont montrĂ© certaines caractĂ©ristiques similaires : une altĂ©ration dans lâexcitabilitĂ© neuronale mise en Ă©vidence par une incidence accrue des dĂ©charges neuronales de type bouffĂ©e, une tendance constante vers la gĂ©nĂ©ralisation, une propagation de plus en plus rapide, une synchronie augmentĂ©e au cours du temps, et une modulation par les Ă©tats de vigilance (facilitation pendant le sommeil Ă ondes lentes et barrage pendant le sommeil REM). Les Ă©tats silencieux, hyper-polarisĂ©s, de neurones corticaux favorisent l'apparition des bouffĂ©es de potentiels dâaction en rĂ©ponse aux Ă©vĂ©nements synaptiques, et l'influence post-synaptique d'une bouffĂ©e de potentiels dâaction est beaucoup plus importante par rapport Ă lâimpacte dâun seul potentiel dâaction. Nous avons Ă©galement apportĂ© des Ă©vidences que les neurones nĂ©ocorticaux de type FRB sont capables Ă rĂ©pondre avec des bouffĂ©es de potentiels dâaction pendant les phases hyper-polarisĂ©es de l'oscillation lente, propriĂ©tĂ© qui peut jouer un rĂŽle trĂšs important dans lâanalyse de lâinformation dans le cerveau normal et dans l'Ă©pileptogenĂšse. Finalement, nous avons rapportĂ© un troisiĂšme mĂ©canisme de plasticitĂ© dans les rĂ©seaux corticaux aprĂšs les crises dâĂ©pilepsie - une diminution dâamplitude des potentiels post-synaptiques excitatrices Ă©voquĂ©es par la stimulation corticale aprĂšs les crises - qui peut ĂȘtre un des facteurs responsables des dĂ©ficits comportementaux observĂ©s chez les patients Ă©pileptiques. Nous concluons que la transition incessante entre des Ă©tats actifs et silencieux dans les circuits cortico-thalamiques induits par disfacilitation (sommeil Ă ondes lentes), dĂ©affĂ©rentation corticale (Ă©pisodes ictales Ă 4-Hz) ou par une stimulation sous-liminale chronique (activitĂ©s paroxysmiques persistantes) crĂ©e des circonstances favorables pour le dĂ©veloppement de l'Ă©pileptogenĂšse. En plus, l'augmentation de lâincidence des bouffĂ©es de potentiels dâactions induisant une excitation post-synaptique anormalement forte, change l'Ă©quilibre entre l'excitation et l'inhibition vers une supra-excitation menant a lâapparition des crises dâĂ©pilepsie.The guiding line in our experiments was the hypothesis that the occurrence and / or the persistence of long-lasting fluctuations between silent and active states in the neocortical networks, together with a modified neuronal excitability are the key factors of epileptogenesis, leading to behavioral seizures. We addressed this hypothesis in two different experimental models. The chronic cortical deafferentation replicated the physiological deafferentation of the neocortex observed during slow-wave sleep (SWS). Under these conditions of decreased synaptic input and increased incidence of silent periods in the corticothalamic system the process of homeostatic plasticity up-regulated cortical cellular and network mechanisms and leaded to an increased excitability. Therefore, the deafferented cortex was able to oscillate between active and silent epochs for long periods of time and, furthermore, to develop highly synchronized activities, ranging from cellular hyperexcitability to focal epileptogenesis and generalized seizures. The kindling model was used in order to impose to the cortical network a synaptic drive superior to the one naturally occurring during the active states - wake or rapid eye movements (REM) sleep. Under these conditions a different plasticity mechanism occurring in the thalamo-cortical system imposed long-lasting oscillatory pattern between active and silent epochs, which we called outlasting activities. Independently of the mechanism of epileptogenesis seizures showed some analogous characteristics: alteration of the neuronal firing pattern with increased bursts probability, a constant tendency toward generalization, faster propagation and increased synchrony over the time, and modulation by the state of vigilance (overt during SWS and completely abolished during REM sleep). Silent, hyperpolarized, states of cortical neurons favor the induction of burst firing in response to depolarizing inputs, and the postsynaptic influence of a burst is much stronger as compared to a single spike. Furthermore, we brought evidences that a particular type of neocortical neurons - fast rhythmic bursting (FRB) class - is capable to consistently respond with bursts during the hyperpolarized phase of the slow oscillation, fact that may play a very important role in both normal brain processing and in epileptogenesis. Finally, we reported a third plastic mechanism in the cortical network following seizures - a decreasing amplitude of cortically evoked excitatory post-synaptic potentials (EPSP) following seizures - which may be one of the factors responsible for the behavioral deficits observed in patients with epilepsy. We conclude that incessant transitions between active and silent states in cortico-thalamic circuits induced either by disfacilitation (sleep), cortical deafferentation (4-Hz ictal episodes) and by kindling (outlasting activities) create favorable circumstances for epileptogenesis. The increase in burst-firing, which further induce abnormally strong postsynaptic excitation, shifts the balance of excitation and inhibition toward overexcitation leading to the onset of seizures
Reciprocal patterning of spontaneous activity and the developing visual cortex
The connections between neurons allow information to be transported throughout the nervous system, whether this information comes from the senses or from stored memories, and whether it leads to decision making or muscle activation. Inaccurate or imprecise wiring between neurons can misroute important information, or cause over- or under-excitation of the nervous system. Connections are initially created during early development, and become fine-tuned as âpracticeâ spontaneous activity strengthens well-placed synapses and prunes aberrant connections. Spontaneous activity is generated by the developing brain itself, and can therefore encode structural information; for instance, neighbouring cells in the retina are more likely to be active at the same time than two cells that are physically further apart. This information can be passed on to other regions of the nervous system, both shaping and being shaped by the developing brain. A connection between two cells is not an all-or-nothing bridge; connections can be strong or weak, and multiple synapses can work together to have a net larger effect on a cell, increasing the likelihood of their activity being passed along. If we record high resolution images of individual neurons, we can actually see connections being formed and regulated in a living animal, with those synapses that do not play along with their neighbours being weakened and removed. In this thesis, I show that connections are preferentially maintained if they are close to other, active connections, creating high activity stretches along the dendrite. I show that the patterning of spontaneous activity relies on a specific type of inhibitory interneuron. Without the activity of these somatostatin-expressing interneurons, spontaneous activations can spread further, activating more cells and a larger proportion of the retinotopic map. Both excitatory and inhibitory activity are required to shape spontaneous activity patterns and restrict activations to a small area of the brain. As adults, we are often acutely aware of our state- whether we are stressed, attentive, or relaxed is something we can physically feel and is reflected in our neural activity. By showing that cholinergic signalling can alter the properties of spontaneous activity, we suggest that state is important even in very young animals. Finally, to causally assert the relationship between spontaneous activity and the developing brain, we developed a wireless tool that allows specific manipulation of activity patterns with minimal interference with natural animal behaviour
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