A neural network model of adaptively timed reinforcement learning and hippocampal dynamics

A neural model is described of how adaptively timed reinforcement learning occurs. The adaptive timing circuit is suggested to exist in the hippocampus, and to involve convergence of dentate granule cells on CA3 pyramidal cells, and NMDA receptors. This circuit forms part of a model neural system for the coordinated control of recognition learning, reinforcement learning, and motor learning, whose properties clarify how an animal can learn to acquire a delayed reward. Behavioral and neural data are summarized in support of each processing stage of the system. The relevant anatomical sites are in thalamus, neocortex, hippocampus, hypothalamus, amygdala, and cerebellum. Cerebellar influences on motor learning are distinguished from hippocampal influences on adaptive timing of reinforcement learning. The model simulates how damage to the hippocampal formation disrupts adaptive timing, eliminates attentional blocking, and causes symptoms of medial temporal amnesia. It suggests how normal acquisition of subcortical emotional conditioning can occur after cortical ablation, even though extinction of emotional conditioning is retarded by cortical ablation. The model simulates how increasing the duration of an unconditioned stimulus increases the amplitude of emotional conditioning, but does not change adaptive timing; and how an increase in the intensity of a conditioned stimulus "speeds up the clock", but an increase in the intensity of an unconditioned stimulus does not. Computer simulations of the model fit parametric conditioning data, including a Weber law property and an inverted U property. Both primary and secondary adaptively timed conditioning are simulated, as are data concerning conditioning using multiple interstimulus intervals (ISIs), gradually or abruptly changing ISis, partial reinforcement, and multiple stimuli that lead to time-averaging of responses. Neurobiologically testable predictions are made to facilitate further tests of the model.Air Force Office of Scientific Research (90-0175, 90-0128); Defense Advanced Research Projects Agency (90-0083); National Science Foundation (IRI-87-16960); Office of Naval Research (N00014-91-J-4100

Biophysical modeling to reverse engineer two mammalian neural circuits lower urinar Y tract and hippocampus

Computational neuroscience provides tools to abstract and generalize principles of neuronal function using mathematics and computers. This dissertation reports biophysical modeling approaches to facilitate reverse engineering of two mammalian neural circuits - the lower urinary tract for the development of stimulation techniques, and the rodent hippocampus to understand mechanisms involved in theta rhythms. The LUT in mammals consists of the urinary bladder, external urethral sphincter (EUS) and the urethra. Control of the LUT is achieved via a neural circuit which integrates distinct components. Dysfunctions of the lower urinary tract (LUT) are caused by a variety of factors including spinal cord injury and diabetes. Our model builds on previous models by using biologically realistic spiking neurons to reproduce neural control of the LUT in both normal function and dysfunction cases. The hippocampus has long been implicated in memory storage and retrieval. Also, hippocampal theta oscillations (4-12 Hz) are consistently recorded during memory tasks and spatial navigation. Previous model revealed five distinct theta generators. The present study extends the work by probing deeper into the intrinsic theta mechanisms via characterizing the mechanisms as being resonant, i.e., inherently produce theta, or synchronizing, i.e., promote coordinated activity, or possibly both. The role of the neuromodulatory state is also investigated.Includes bibliographical references (pages 157-164)

Sensory gating in the hippocampus and the medial prefrontal cortex

Sensory gating is a mechanism by which irrelevant sensory information is filtered in the brain, enabling efficient information processing. The auditory conditioning-test paradigm, an index of sensory gating, measures the reduction in the auditory-evoked response (AER) produced by a test stimulus following an initial conditioning stimulus. Schizophrenic patients demonstrate a lack of attenuation of the test response measured in the P50 component of the cortical auditory-evoked potential. The N2/N40 auditory-evoked potential recorded from rat hippocampus is considered homologous to the human P50 wave. Altered glutamatergic neurotransmission and the endocannabinoid system have been implicated in the pathogenesis of schizophrenia with structural and functional abnormalities in the hippocampus and the medial prefrontal cortex (mPFC). The current study examined sensory gating using auditory conditioning-test paradigm in the dentate gyrus (DG) and the CA3 region of the hippocampus and in the medial prefrontal cortex (mPFC) before and after administration of N-Methyl- D-Aspartate (NMDA) receptor antagonist phencyclidine (PCP; 1 mg/kg, i.p) or the cannabinoid agonist WIN55,212-2 (1.2mg/kg, i.p). Electrophysiological recordings were conducted in Lister hooded rats, under isoflurane anaesthesia, during the presentation of paired auditory stimuli. Extracellular action potential spikes and local field potentials (LFPs) were recorded simultaneously using multi-electrode arrays and the effects of acute administration of PCP (1 mg/kg, i.p) or WIN55,212-2 (1.2mg/kg, i.p) was determined. Gating of the N2 wave was assessed by measuring the ratio of the Test to Conditioning response amplitude (T/C ratio); T/C ratio ≤ 50% was indicative of gating. Robust auditory-evoked potentials were recorded from the hippocampal CA3 and DG regions and the mPFC; some rats demonstrated auditory gating while others failed to. In rats that demonstrated gating of N2, mPFC showed higher T/C ratios and shorter conditioning response latencies compared to DG and CA3. PCP disrupted auditory gating in all three areas with a significant increase in test response amplitudes in the gating rats. PCP had no effect on T/C ratios in the non-gating rats. The atypical antipsychotic clozapine (5mg/kg, i.p) prevented PCP induced disruption of gating in the CA3, DG and mPFC. WIN55,212-2 disrupted auditory gating with a significant increase in test response amplitudes in the gating rats. WIN55,212-2 had no effect on T/C ratios in the non-gating rats. The cannabinoid receptor (CB1) antagonist SR141716A (1mg/kg, i.p) prevented WIN55,212-2 induced disruption of gating. Neither clozapine nor SR141716A had any effects on the non-gating rats. Both PCP and WIN55,212- 2 disrupted gating of the single-unit responses in the CA3, DG and mPFC, effects which were prevented by the pre- administration of clozapine or SR141716A. The non-gating rats may model some inhibitory deficits observed in schizophrenic patients. Administration of PCP disrupted auditory gating which was prevented by clozapine; similar deficits are observed in schizophrenic patients. Furthermore, cannabinoid receptor activation disrupted auditory gating which was prevented by CB1 receptor antagonism, suggesting the endocannabinoid system as a potential target for future clinical research in the treatment in schizophrenia

Specific disruption of hippocampal mossy fiber synapses in a mouse model of familial Alzheimer's disease.

The earliest stages of Alzheimer's disease (AD) are characterized by deficits in memory and cognition indicating hippocampal pathology. While it is now recognized that synapse dysfunction precedes the hallmark pathological findings of AD, it is unclear if specific hippocampal synapses are particularly vulnerable. Since the mossy fiber (MF) synapse between dentate gyrus (DG) and CA3 regions underlies critical functions disrupted in AD, we utilized serial block-face electron microscopy (SBEM) to analyze MF microcircuitry in a mouse model of familial Alzheimer's disease (FAD). FAD mutant MF terminal complexes were severely disrupted compared to control - they were smaller, contacted fewer postsynaptic spines and had greater numbers of presynaptic filopodial processes. Multi-headed CA3 dendritic spines in the FAD mutant condition were reduced in complexity and had significantly smaller sites of synaptic contact. Significantly, there was no change in the volume of classical dendritic spines at neighboring inputs to CA3 neurons suggesting input-specific defects in the early course of AD related pathology. These data indicate a specific vulnerability of the DG-CA3 network in AD pathogenesis and demonstrate the utility of SBEM to assess circuit specific alterations in mouse models of human disease

A különböző gátlósejttípusok hozzájárulása a hippokampális éleshullámok kialakulásához. = Contribution by distinct types of GABAergic interneuron to hippocampal sharp wave/ripple oscillations.

A hippokampusz neuronhálózatában spontán keletkeznek az éleshullámok, amelyek kulcsszerepet játszanak a memóriafolyamatokban. Egy in vitro modellt használva feltérképeztük az egyes idegsejttípusok bemeneti és kimeneti tulajdonságait az éleshullámok alatt. Az találtuk, hogy a legaktívabb gátlósejtek parvalbumint tartalmaztak, míg a piramissejtek többsége nem tüzelt. Meghatároztuk, hogy az éleshullámok alatti tüzelési aktivitás korrelált a serkentő szinaptikus bemenettel. Farmakológiai kísérletekkel kiderítettük, hogy a parvalbumin tartalmú gátlósejtek nagyfrekvenciás kisüléséből eredő periszomatikus gátló áramok generálják a lokális mezőpotenciálban mérhető éleshullámokat. Hasonlóan, ezek a gátlósejtek felelősek a gamma oszcillációk létrehozásáért is a hippokampális agyszeletekben. Ezen túlmenően megállapítottuk, hogy a kolinerg receptorok aktivációja, amely növeli a serkenthetőséget, de csökkenti a szinaptikus kommunikáció hatékonyságát, képes a hippokampusz alapműködését, az éleshullám-aktivitást átkapcsolni gamma oszcillációvá. Az eredményeink azt mutatják, hogy az éber állatra jellemző hálózati aktivitásokat, az éleshullámokat és a gamma oszcillációt ugyan az a hippokampális neuronhálózat generálja, amely a piramissejtek és a parvalbumin tartamú gátlósejtekből áll. | Sharp wave/ripple oscillations (SPW-Rs), that play a crucial role in memory formation, are spontaneously emerging synchronous network events in the hippocampal circuitry. Using an in vitro model, we uncovered that the input-output properties of distinct types of neurons during SPW-Rs. We found that the most active GABAergic cells were parvalbumin containing interneurons, while the vast majority of pyramidal cells was silent. Our analysis revealed that in all cell types the firing during SPW-Rs was driven by excitatory synaptic input. Pharmacological manipulations uncovered that perisomatic inhibitory currents predominantly originated from the high frequency discharge of parvalbumin containing interneurons generate the majority of the field potential that is seen as a sharp wave. Similarly, these GABAergic cells were found to generate the gamma oscillations in hippocampal slices as well. In addition, we elucidated that by cholinergic receptor activation, which increases the excitability, but reduces the efficiency of synaptic communication, the default mode of the hippocampal operation, the SPW-R state can be readily switched to gamma oscillation. Our results propose that the behaviorally relevant network activities, SPW-Rs and gamma oscillations are generated by the same neuronal circuitries in the hippocampus, comprised of pyramidal cells and parvalbumin containing interneurons

Sensory gating in the hippocampus and the medial prefrontal cortex

Sensory gating is a mechanism by which irrelevant sensory information is filtered in the brain, enabling efficient information processing. The auditory conditioning-test paradigm, an index of sensory gating, measures the reduction in the auditory-evoked response (AER) produced by a test stimulus following an initial conditioning stimulus. Schizophrenic patients demonstrate a lack of attenuation of the test response measured in the P50 component of the cortical auditory-evoked potential. The N2/N40 auditory-evoked potential recorded from rat hippocampus is considered homologous to the human P50 wave. Altered glutamatergic neurotransmission and the endocannabinoid system have been implicated in the pathogenesis of schizophrenia with structural and functional abnormalities in the hippocampus and the medial prefrontal cortex (mPFC). The current study examined sensory gating using auditory conditioning-test paradigm in the dentate gyrus (DG) and the CA3 region of the hippocampus and in the medial prefrontal cortex (mPFC) before and after administration of N-Methyl- D-Aspartate (NMDA) receptor antagonist phencyclidine (PCP; 1 mg/kg, i.p) or the cannabinoid agonist WIN55,212-2 (1.2mg/kg, i.p). Electrophysiological recordings were conducted in Lister hooded rats, under isoflurane anaesthesia, during the presentation of paired auditory stimuli. Extracellular action potential spikes and local field potentials (LFPs) were recorded simultaneously using multi-electrode arrays and the effects of acute administration of PCP (1 mg/kg, i.p) or WIN55,212-2 (1.2mg/kg, i.p) was determined. Gating of the N2 wave was assessed by measuring the ratio of the Test to Conditioning response amplitude (T/C ratio); T/C ratio ≤ 50% was indicative of gating. Robust auditory-evoked potentials were recorded from the hippocampal CA3 and DG regions and the mPFC; some rats demonstrated auditory gating while others failed to. In rats that demonstrated gating of N2, mPFC showed higher T/C ratios and shorter conditioning response latencies compared to DG and CA3. PCP disrupted auditory gating in all three areas with a significant increase in test response amplitudes in the gating rats. PCP had no effect on T/C ratios in the non-gating rats. The atypical antipsychotic clozapine (5mg/kg, i.p) prevented PCP induced disruption of gating in the CA3, DG and mPFC. WIN55,212-2 disrupted auditory gating with a significant increase in test response amplitudes in the gating rats. WIN55,212-2 had no effect on T/C ratios in the non-gating rats. The cannabinoid receptor (CB1) antagonist SR141716A (1mg/kg, i.p) prevented WIN55,212-2 induced disruption of gating. Neither clozapine nor SR141716A had any effects on the non-gating rats. Both PCP and WIN55,212- 2 disrupted gating of the single-unit responses in the CA3, DG and mPFC, effects which were prevented by the pre- administration of clozapine or SR141716A. The non-gating rats may model some inhibitory deficits observed in schizophrenic patients. Administration of PCP disrupted auditory gating which was prevented by clozapine; similar deficits are observed in schizophrenic patients. Furthermore, cannabinoid receptor activation disrupted auditory gating which was prevented by CB1 receptor antagonism, suggesting the endocannabinoid system as a potential target for future clinical research in the treatment in schizophrenia

Glycine receptors in CNS neurons as a target for nonretrograde action of cannabinoids

At many central synapses, endocannabinoids released by postsynaptic cells act retrogradely on presynaptic G-protein-coupled cannabinoid receptors to inhibit neurotransmitter release. Here, we demonstrate that cannabinoids may directly affect the functioning of inhibitory glycine receptor (GlyR) channels. In isolated hippocampal pyramidal and Purkinje cerebellar neurons, endogenous cannabinoids anandamide and 2-arachidonylglycerol, applied at physiological concentrations, inhibited the amplitude and altered the kinetics of rise time, desensitization, and deactivation of the glycine-activated current (