The Rescorla-Wagner Drift-Diffusion Model

Computational models of classical conditioning have made significant contributions to the theoretic understanding of associative learning, yet they still struggle when the temporal aspects of conditioning are taken into account. Interval timing models have contributed a rich variety of time representations and provided accurate predictions for the timing of responses, but they usually have little to say about associative learning. In this thesis we present a unified model of conditioning and timing that is based on the influential Rescorla-Wagner conditioning model and the more recently developed Timing Drift-Diffusion model. We test the model by simulating 11 experimental phenomena and show that it can provide an adequate account for 9, and a partial account for the other 2. We argue that the model can account for more phenomena in the chosen set than these other similar in scope models: CSCTD, MS-TD, Learning to Time and Modular Theory. A comparison and analysis of the mechanisms in these models is provided, with a focus on the types of time representation and associative learning rule used

Normal And Epilepsy-Associated Pathologic Function Of The Dentate Gyrus

The dentate gyrus plays critical roles both in cognitive processing and in regulating propagation of pathological, synchronous activity through the limbic system. The cellular and circuit mechanisms underlying these diverse functions overlap extensively. At the cellular level, the intrinsic properties of dentate granule cells combine to make these neurons fundamentally reluctant to activate, one of their hallmark traits. At the circuit level, the dentate gyrus is one of the more heavily inhibited regions of the brain, with powerful feedforward and feedback GABAergic inhibition dominating responses to afferent activation. In pathologic states such as epilepsy, disease-associated alterations within the dentate gyrus combine to compromise this circuit’s regulatory properties, culminating in a collapse of its normal function. Through the use of dynamic circuit imaging and electrophysiological brain slice recordings, pharmacology, immunohistochemistry, and a pilocarpine model of epilepsy, I characterize the emergence of dentate granule cell firing properties during brain development and then examine how the circuit’s normal activation properties become corrupted as epilepsy develops. I find that, in the perinatal brain, dentate granule cells activate in large numbers. As animals mature, these cells become less excitable and activate in extremely sparse populations in a precise, repeatable, frequency-dependent manner. This sparse activation is mediated by local circuit inhibition and not by alterations in afferent innervation of granule cells. Later, in a pilocarpine model of epilepsy, I demonstrate that normally sparse granule cell activation is massively enhanced during both epilepsy development and expression. This augmentation in excitability is mediated primarily by local disinhibition, and the mechanistic cause of this compromised inhibitory function varies over time following epileptogenic injury. My results implicate a reduction in chloride ion extrusion as a mechanism compromising inhibitory function and contributing to granule cell hyperactivation specifically during early epilepsy development. In contrast, we demonstrate that sparse dentate granule cell activation in chronically epileptic mice is rescued by glutamine application, implicating compromised GABA synthesis as a mechanism of disinhibition in chronic epilepsy. We conclude that compromised feedforward inhibition within the local circuit is the predominant mediator of the massive dentate gyrus circuit hyperactivation evident in animals during and following epilepsy development

The functional logic of corticostriatal connections

Unidirectional connections from the cortex to the matrix of the corpus striatum initiate the cortico-basal ganglia (BG)-thalamocortical loop, thought to be important in momentary action selection and in longer-term fine tuning of behavioural repertoire; a discrete set of striatal compartments, striosomes, has the complementary role of registering or anticipating reward that shapes corticostriatal plasticity. Re-entrant signals traversing the cortico-BG loop impact predominantly frontal cortices, conveyed through topographically ordered output channels; by contrast, striatal input signals originate from a far broader span of cortex, and are far more divergent in their termination. The term ‘disclosed loop’ is introduced to describe this organisation: a closed circuit that is open to outside influence at the initial stage of cortical input. The closed circuit component of corticostriatal afferents is newly dubbed ‘operative’, as it is proposed to establish the bid for action selection on the part of an incipient cortical action plan; the broader set of converging corticostriatal afferents is described as contextual. A corollary of this proposal is that every unit of the striatal volume, including the long, C-shaped tail of the caudate nucleus, should receive a mandatory component of operative input, and hence include at least one area of BG-recipient cortex amongst the sources of its corticostriatal afferents. Individual operative afferents contact twin classes of GABAergic striatal projection neuron (SPN), distinguished by their neurochemical character, and onward circuitry. This is the basis of the classic direct and indirect pathway model of the cortico-BG loop. Each pathway utilises a serial chain of inhibition, with two such links, or three, providing positive and negative feedback, respectively. Operative co-activation of direct and indirect SPNs is, therefore, pictured to simultaneously promote action, and to restrain it. The balance of this rival activity is determined by the contextual inputs, which summarise the external and internal sensory environment, and the state of ongoing behavioural priorities. Notably, the distributed sources of contextual convergence upon a striatal locus mirror the transcortical network harnessed by the origin of the operative input to that locus, thereby capturing a similar set of contingencies relevant to determining action. The disclosed loop formulation of corticostriatal and subsequent BG loop circuitry, as advanced here, refines the operating rationale of the classic model and allows the integration of more recent anatomical and physiological data, some of which can appear at variance with the classic model. Equally, it provides a lucid functional context for continuing cellular studies of SPN biophysics and mechanisms of synaptic plasticity