Randal A. Koene

Cholinergic Deafferentation of the Entorhinal Cortex in Rats Impairs Encoding of Novel But Not Familiar Stimuli in a Delayed Nonmatch-to-Sample Task

Acetylcholine may regulate working memory for novel stimuli by activating intrinsic mechanisms for sustained spiking in entorhinal cortical neurons, which have been demonstrated in slice preparations of the entorhinal cortex. Computational modeling demonstrates that loss of the cholinergic activation of intrinsic mechanisms for sustained activity could selectively impair working memory for novel stimuli, whereas working memory for familiar stimuli could be maintained because of previously modified synapses. Blockade of muscarinic cholinergic receptors and selective cholinergic lesions has been shown to impair encoding in delayed matching tasks. However, previous studies have not compared explicitly the role of cholinergic modulation in working memory for novel versus familiar stimuli. Here, we show that lesions of the cholinergic innervation of the entorhinal cortex selectively impair delayed nonmatch to sample performance for novel odors, whereas delayed nonmatch to sample for familiar odors is spared. This indicates an important role for cholinergic innervation of the entorhinal cortex in working memory for novel stimuli.

Modeling goal-directed spatial navigation in the rat based on physiological data from the hippocampal formation

We investigated the importance of hippocampal theta oscillations and the significance of phase differences of theta modulation in the cortical regions that are involved in goal-directed spatial navigation. Our models used representations of entorhinal cortex layer III (ECIII), hippocampus and prefrontal cortex (PFC) to guide movements of a virtual rat in a virtual environment. The model encoded representations of the environment through long-term potentiation of excitatory recurrent connections between sequentially spiking place cells in ECIII and CA3. This encoding required buffering of place cell activity, which was achieved by a short-term memory (STM) in EC that was regulated by theta modulation and allowed synchronized reactivation with encoding phases in ECIII and CA3. Inhibition at a specific theta phase deactivated the oldest item in the buffer when new input was presented to a full STM buffer. A 180 degrees phase difference separated retrieval and encoding in ECIII and CA3, which enabled us to simulate data on theta phase precession of place cells. Retrieval of known paths was elicited in ECIII by input at the retrieval phase from PFC working memory for goal location, requiring strict theta phase relationships with PFC. Known locations adjacent to the virtual rat were retrieved in CA3. Together, input from ECIII and CA3 activated predictive spiking in cells in CA1 for the next desired place on a shortest path to a goal. Consistent with data, place cell activity in CA1 and CA3 showed smaller place fields than in ECIII.

From biophysics to behavior: Catacomb2 and the design of biologically-plausible models for spatial navigation.

A variety of approaches are available for using computational models to help understand neural processes over many levels of description, from sub-cellular processes to behavior. Alongside purely deductive bottom-up or top-down modeling, a systems design strategy has the advantage of providing a clear goal for the behavior of a complex model. The order in which biological details are added is dictated by functional requirements in terms of the tasks that the model should perform. Ideas from engineering can be mixed with those from biology to build systems in which some constituents are modeled in detail using biologically-realistic components, while others are implemented directly in software. This allows the areas of most interest to be studied within the context of a behaving system in which each component is constrained both by the biology it is intended to represent as well as the task it is required to perform within the system. The Catacomb2 modeling package has been developed to allow rapid and flexible design and study of complex multi-level systems ranging in scale from ion channels to whole animal behavior. The methodology, internal architecture, and capabilities of the system are described.Its use is illustrated by a modeling case study in which hypotheses about how parahippocampal and hippocampal structures may be involved in spatial navigation tasks are implemented in a model of a virtual rat navigating through a virtual environment in search of a food reward. The model incorporates theta oscillations to separate encoding from retrieval and yields testable predictions about the phase relations of spiking activity to theta oscillations in different parts of the hippocampal formation at various stages of the behavioral task.

2008 Special Issue: Reversed and forward buffering of behavioral spike sequences enables retrospective and prospective retrieval in hippocampal regions CA3 and CA1

We propose a mechanism to explain both retrospective and prospective recall activity found in experimental data from hippocampal regions CA3 and CA1. Our model of temporal context dependent episodic memory replicates reverse recall in CA1, as recently recorded and published [Foster, D., & Wilson, M. (2006). Reverse replay of behavioural sequences in hippocampal place cells during the awake state. Nature, 440, 680-683], as well as the prospective and retrospective activity recorded in region CA3 during spatial tasks [Johnson, A., & Redish, A. (2006). Neural ensembles in ca3 transiently encode paths forward of the animal at a decision point: a possible mechanism for the consideration of alternatives. In 2006 neuroscience meeting planner. Atlanta, GA: Society for Neuroscience. (Program no. 574.2)]. We suppose that CA3 encodes episodic memory of both forward and reversed sequences of perforant path spikes representing place input. Using a persistent firing buffer mechanism in layer II of entorhinal cortex, simulated episodic learning involves dentate gyrus, layer III of entorhinal cortex, and hippocampal regions CA3 and CA1. Associations are formed between buffered episodic cues, unique temporal context specific representations in dentate gyrus, and episodic memory in the CA3 recurrent network.

Consequences of parameter differences in a model of short-term persistent spiking buffers provided by pyramidal cells in entorhinal cortex

In previous simulations of hippocampus-dependent and prefrontal cortex-dependent tasks, we demonstrated the use of one-shot short-term buffering with time compression that may be achieved through persistent spiking activity during theta rhythm. A biophysically plausible implementation of such a first-in first-out buffer of short sequences of spike patterns includes noise and differences between the parameter values of individual model pyramidal cells. We show that a specific set of parameters determines model buffer capacity and buffer function, and individual differences can have consequences similar to those of noise. The set of parameters includes the frequency of network theta rhythm and the strength of recurrent inhibition (affecting capacity), as well as the time constants of the characteristic after-depolarizing response and the phase of afferent input during theta rhythm (affecting buffer function). Given a sufficient number of pyramidal cells in layer II of entorhinal cortex, and in each self-selected category of pyramidal cells with similar model parameters, buffer function within a category is reliable with category-specific properties. Properties include buffering of spikes in the order of inputs or in the reversed order. Multiple property sets may enable parallel buffers with different capacities, which may underlie differences of place field sizes and may interact with grid cell firing in a separate population of layer II stellate cells in the entorhinal cortex.

Goal-directed spatial navigation of the rat depends on phases of theta oscillation in hippocampal circuitry

We investigated the importance of hippocampal theta oscillations and the significance of phase differences of theta modulation in the cortical regions that are involved in goal-directed spatial navigation. A model of the rat entorhinal and hippocampal circuitry was created to achieve this. Recurrent fibres between sequentially spiking place cells in ECIII and CA3 established LTP through Hebbian learning that encoded paths through the environment that lead through a goal. Input at arbitrary times during exploration of the environment needed to be repeated as ordered sequences of spikes. A short-term memory (STM) buffer in EC, regulated by theta modulation achieved this and synchronized reactivation with encoding phases in ECIII and CA3. Inhibition at a specific theta phase deactivates the oldest item in the buffer when new input was represented to a full STM buffer. A 180 degree phase difference separated retrieval and encoding in ECIII and CA3, which enabled us to simulate bi-phasic theta phase precession of place cells. Retrieval of known paths was elicited in ECIII by input at the retrieval phase from a PFC storage of goal location. Known locations adjacent to the virtual rat were retrieved in CA3. Together, these activated predictive spiking cells in CA1 for the next desired place on a shortest path to a goal. Consistent with data, place cell activity in CA1 and CA3 showed smaller place fields than in ECIII.

A reversing buffer mechanism that enables instances of retrospective activity in hippocampal regions CA3 and CA1

We simulate temporal context dependent episodic memory with resulting reversed order activity in model hippocampal regions CA3 and CA1, similar to recorded activity recently published by D.J.Foster and M.A.Wilson. Our model supposes that encoding of reversed place associations in CA3 is the cause of that activity. That proposed mechanism is the focus of this paper, and we simulate resulting activity in model layer III of entorhinal cortex, and in hippocampal regions CA3 and CA1. Learning associates spike episodes maintained in a persistent firing buffer in layer II of entorhinal cortex (ECU) with unique temporal context specific representations formed in dentate gyrus (DG), as well as with episodic memory encoded in the CA3 recurrent network. Similarly, spiking representations in DG are associated with episodic memory in CA3. Spike sequences retrieved in CA3 are reversed representations of the original episodic input. As observed by Foster and Wilson, and in more recent electrophysiology, resulting simulated activity in CA1 exhibits some forward and some reversed spiking.

An integrate and fire model of prefrontal cortex provides a biological implementation of action selection in reinforcement learning theory that reuses known representations

Task specific spiking activity that is selective for specific perceptions and actions is observed in the pre frontal cortex (PFC) of primates and rats during goal-directed behavior. A spiking neuron model of minicolumn circuits in PFC has been shown to successfully replicate the performance and categories of selective neuronal responses recorded in a primate visual discrimination task. The model provides a biological implementation of the action selection process used in reinforcement learning theory. Using this model, we propose a mechanistic explanation based on the reuse of previous encoding in PFC minicolumns for the ability to find short-cuts during the learning of some novel goal-directed tasks, but not others.