The primary motor cortex (M1) is an important site for learning new motor skills. While rewardis known to both enhance and accelerate motor learning, the mechanism by which reward exertsthese effects remains unclear. Previous studies in primates have demonstrated reward-relatedactivity in M1, however, it is not known whether reward is represented among different neuronalcell types in M1, or if the representations change over the course of reward-based associativelearning. We begin by reviewing advances in optogenetic methods that have enabled thedissection of cortical circuits underlying sensorimotor behaviours with a special focus on thefunctional roles of cell-type specific connections in governing sensorimotor informationprocessing and learning and memory. We then used in vivo, two-photon calcium imaging tocharacterize reward and reward-related responses in pyramidal neurons (PNs), PV-INs, SST-INsand VIP-INs while mice simultaneously performed a head-fixed auditory classical conditioningtask. We found that different cell types had distinct responses to the conditioned stimulus (CS)and to reward, and these responses underwent differential changes over the course of associativelearning. Notably, VIP-INs preferentially represented reward and their reward responsesincreased with learning, while PV-INs preferentially represented the CS, and their CS responsesincreased with learning. Lastly, to identify which brain regions might provide reward-relatedinput to VIP-INs, we performed cell-type specific monosynaptic rabies tracing and generatedcomparative brain-wide maps of input to VIP-INs, PV-INs, SST-INs and PNs in M1. Weidentified preferential input from the orbital frontal cortex (ORB) to VIP-INs compared to theother IN subtypes. These results suggest that ORB may convey reward-related input to VIP-INsand thereby disinhibit local MOP circuitry during reward-based learning. Together, these studiesprovide a potential mechanism for how reward modulates motor learning.

No description available.

Thesis (Ph. D.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains viii, 143 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references.

L’élément constitutif des synapses centrales est le site synaptique individuel, comprenant une zone active du côté présynaptique et une densité postsynaptique associée. Du fait de limitations techniques nos connaissances sur le mode de fonctionnement d’un site synaptique restent insuffisantes. Pour faire progresser cette question nous projetons d’effectuer des enregistrements en paires entre interneurones de la couche moléculaire du cervelet. Ces neurones forment des synapses qui ont des signaux élémentaires quantiques de grande taille, et les synapses comprennent parfois un seul site synaptique, ce qui fait qu’ils offrent des avantages décisifs pour ce projet. Les réponses postsynaptiques à des trains de potentiels d’action seront étudiées dans différentes conditions expérimentales. Les résultats seront interprétés par un modèle supposant que les vésicules synaptiques doivent se lier à un petit groupe de sites d’arrimage avant l’exocytose. / The unitary element of central synaptic transmission is a single synaptic site, with one active zone as presynaptic component and the postsynaptic density as postsynaptic partner. Due to technical limitations there is much uncertainty on the mode of functioning of a single synaptic site. To address this issue it is planned to perform paired recordings between interneurons of the molecular layers of the cerebellum. These neurons form synapses with a large quantal size, and occasionally displaying a single release site, and are thus favorable for this study. Postsynaptic responses will be studied in response to trains of presynaptic action potentials under various conditions. The results will be compared to a model supposing the obligatory binding of vesicles to a small complement of docking sites prior to exocytosis.

No description available.

A large percentage of individuals with intractable epilepsies have an accompanying cortical malformation, the underlying cellular mechanisms of which are poorly understood. It is known however that in an animal model for one such malformation, polymicrogyria, epileptogenesis occurs most easily from an adjacent area termed the paramicrogyral region (PMR). Previous studies implicate SS interneurons as a potential contributor to this pathology, which lead to our hypothesis: in PMR, SS interneurons exert a higher modulatory influence on excitatory pyramidal cells, as compared to the same by SS interneurons within homologous control cortex. Using a freeze-lesion model for polymicrogyria in transgenic mice that selectively express either Channelrhodopsin or Archaerhodopsin optogenetic channels in these cells, we assessed the contribution of SS interneurons as it potentially differs between layer V of PMR and control cortex. These studies provided the following biological examples in support of previous extrapolations that indicate SS over-activation within PMR: (1) SS interneuron mediated evocation of inhibitory events in layer V excitatory neurons is more robust in PMR than in control. Similarly, electrically-evoked inhibitory events in these excitatory neurons trend towards being larger, signifying a larger contribution by interneurons. (2) SS interneuron mediated suppression of electrically-evoked responses trends towards being stronger in PMR; and (3) the selective silencing of SS interneurons might not impart an effect on spontaneous inhibitory postsynaptic events.

Epilepsy, defined by recurrent seizures, is the one of the most prevalent neurological disorders worldwide (World Health Organization 2007). While many forms of epilepsy are well-controlled by anti-epileptogenic medications, a significant portion of patients have intractable, i.e. untreatable, seizures. The etiology of these seizures is varied, but a significant cause, particularly for patients with intractable epilepsy is developmental malformation. In these cases, an error or interruption during the development of the neocortex produces a structural alteration. Such patients may have other neurological problems, but seizures are the most common symptom. The neuronal mechanisms that link malformation and cortical hyperexcitability are not well understood. Here we have sought to examine potential mechanisms that result from microgyria, a malformation characterized by excessive numbers of small gyri.The presence of epileptiform activity indicates that the normal balance of excitation and inhibition has shifted . Two functions of inhibition within neocortex are to prevent spread of excitation, and to modulate the timing of surrounding excitation. Although seemingly contradictory, increasing some forms of inhibition can result in an increase in synchronous excitatory activity. We hypothesize that for certain malformation epilepsies, the inhibitory processes that control timing are increased, creating a hyper-synchronous cortex, while the inhibitory processes that control horizontal spread are decreased, allowing the propagation of such activity. Here we have examined the network effect of selectively modulating the inhibitory cells that control vertical or columnar cortical synchrony. This modulation is performed via activation of metabotropic glutamate receptors found on the vertically-projecting interneurons but not on those inhibitory cells that control horizontal spread of activity. Our results suggest that the network effect of activating these interneurons is altered in malformed, epileptogenic cortex.

Use-dependent long-term plasticity in synaptic connections represents the cellular substrate for learning and memory. The hippocampus is the most thoroughly investigated brain area for long-term synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) are both well characterized in glutamatergic excitatory connections between hippocampal principal cells in vitro and in vivo. An increasing number of studies based on acute brain slice preparations report LTP and LTD in excitatory synapses onto postsynaptic hippocampal GABAergic inhibitory interneurons. However, a systematic study of activity-induced long-term plasticity in excitatory synaptic connections to inhibitory GABAergic interneurons in vivo is missing. To determine whether LTP and LTD occur in excitatory synaptic connections to the hippocampal CA1 area GABAergic interneurons types in intact brain, I have used juxtacellular recording to measure synaptically evoked short-delay postsynaptic action potential probability in identified CA1 neurons in the urethane-anaesthetized rats. Plasticity in excitatory synaptic connections to CA1 cell types was measured as a change of afferent pathway stimulation-evoked postsynaptic spike probability and delay. In the study only experiments with monosynaptic-like short-delay (range 3-12 ms) postsynaptic spikes phase-locked to afferent stimulation were used. Afferent fibres were stimulated from the CA1 area of the hippocampus at the contralateral (left) side to avoid simultaneous monosynaptic activation of GABAergic fibres and to exclude antidromic spikes in recorded CA1 cells (in right hemisphere). Plasticity in pathways was tested using theta-burst high-frequency stimulation (TBS, 100 pulses), which is one of the most common synaptic plasticity induction protocols in acute brain slice studies. I discovered that TBS elicited permanent potentiation in single shock-evoked postsynaptic spike probability with shortening or no change in evoked spike latency in various postsynaptic neuron types including three identified pyramidal cells and parvalbumin-expressing (PV+) interneurons. Most fast-spiking PV+ cells showed LTP including an axo-axonic cell and one bistratified cell, whereas two identified basket cells exhibited LTD in similar experimental conditions. In addition, I discovered diverse plasticity in non-fast spiking interneurons, reporting LTP in an ivy cell, and LTD in three incompletely identified regular-spiking CA1 interneurons. I report that the underlying brain state, defined as theta oscillation (3-6 Hz) or non-theta in local field potential, failed to explain whether LTP, LTD or no plasticity was generated in interneurons. The results show that activity-induced potentiation and depression similar to LTP and LTD also occur in excitatory synaptic pathways to various CA1 interneurons types in vivo. I propose that long-term plasticity in excitatory connections to inhibitory interneurons may be take place in learning and memory processes in the hippocampus.

The hippocampus is one of the most intensely studied brain structures and the oscillatory activity of the hippocampal neurons is believed to be involved in learning and memory consolidation. Therefore, studying rhythm generation and modulation in this structure is an important step in understanding its function. In this thesis, these phenomena are studied via mathematical models of networks of hippocampal interneurons. The two types of neural networks considered here are homogenous and heterogenous networks. In homogenous networks, the input current to each neuron is equal, while in heterogenous networks, this assumption is relaxed and there is a specified degree of heterogeneity in the input stimuli. A phase reduction technique is applied to the neural network model of the hippocampal interneurons and attempts are made to understand the implications of heterogeneity to the existence and stability of the synchronized oscillations. The Existence of a critical level of heterogeneity above which the synchronized rhythms are not stable is established, and linear analysis is applied to derive expressions for estimating the perturbations in the network frequency and timing of the neural spikes. The mathematical techniques developed in this thesis are general enough to be applied to models describing other types of neurons not considered here. Possible biological implications include the application of high frequency local stimulation to alleviate the synchronous neural oscillations in pathological conditions such as epilepsy and Parkinson's disease and the possible role of heterogeneity in controlling the rhythm frequency and switching between various cognitive states.

The hippocampus is one of the most intensely studied brain structures and the oscillatory activity of the hippocampal neurons is believed to be involved in learning and memory consolidation. Therefore, studying rhythm generation and modulation in this structure is an important step in understanding its function. In this thesis, these phenomena are studied via mathematical models of networks of hippocampal interneurons. The two types of neural networks considered here are homogenous and heterogenous networks. In homogenous networks, the input current to each neuron is equal, while in heterogenous networks, this assumption is relaxed and there is a specified degree of heterogeneity in the input stimuli. A phase reduction technique is applied to the neural network model of the hippocampal interneurons and attempts are made to understand the implications of heterogeneity to the existence and stability of the synchronized oscillations. The Existence of a critical level of heterogeneity above which the synchronized rhythms are not stable is established, and linear analysis is applied to derive expressions for estimating the perturbations in the network frequency and timing of the neural spikes. The mathematical techniques developed in this thesis are general enough to be applied to models describing other types of neurons not considered here. Possible biological implications include the application of high frequency local stimulation to alleviate the synchronous neural oscillations in pathological conditions such as epilepsy and Parkinson's disease and the possible role of heterogeneity in controlling the rhythm frequency and switching between various cognitive states.