The hippocampus and cerebellum in adaptively timed learning, recognition, and movement

The concepts of declarative memory and procedural memory have been used to distinguish two basic types of learning. A neural network model suggests how such memory processes work together as recognition learning, reinforcement learning, and sensory-motor learning take place during adaptive behaviors. To coordinate these processes, the hippocampal formation and cerebellum each contain circuits that learn to adaptively time their outputs. Within the model, hippocampal timing helps to maintain attention on motivationally salient goal objects during variable task-related delays, and cerebellar timing controls the release of conditioned responses. This property is part of the model's description of how cognitive-emotional interactions focus attention on motivationally valued cues, and how this process breaks down due to hippocampal ablation. The model suggests that the hippocampal mechanisms that help to rapidly draw attention to salient cues could prematurely release motor commands were not the release of these commands adaptively timed by the cerebellum. The model hippocampal system modulates cortical recognition learning without actually encoding the representational information that the cortex encodes. These properties avoid the difficulties faced by several models that propose a direct hippocampal role in recognition learning. Learning within the model hippocampal system controls adaptive timing and spatial orientation. Model properties hereby clarify how hippocampal ablations cause amnesic symptoms and difficulties with tasks which combine task delays, novelty detection, and attention towards goal objects amid distractions. When these model recognition, reinforcement, sensory-motor, and timing processes work together, they suggest how the brain can accomplish conditioning of multiple sensory events to delayed rewards, as during serial compound conditioning.Air Force Office of Scientific Research (F49620-92-J-0225, F49620-86-C-0037, 90-0128); Advanced Research Projects Agency (ONR N00014-92-J-4015); Office of Naval Research (N00014-91-J-4100, N00014-92-J-1309, N00014-92-J-1904); National Institute of Mental Health (MH-42900

Linking Visual Cortical Development to Visual Perception

Defense Advanced Research Projects Agency and the Office of Naval Research (N00014-95-1-0409); National Science Foundation (IRI-97-20333); Office of Naval Research (N00014-95-1-0657

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

Task-phase-specific dynamics of basal forebrain neuronal ensembles.

Cortically projecting basal forebrain neurons play a critical role in learning and attention, and their degeneration accompanies age-related impairments in cognition. Despite the impressive anatomical and cell-type complexity of this system, currently available data suggest that basal forebrain neurons lack complexity in their response fields, with activity primarily reflecting only macro-level brain states such as sleep and wake, onset of relevant stimuli and/or reward obtainment. The current study examined the spiking activity of basal forebrain neuron populations across multiple phases of a selective attention task, addressing, in particular, the issue of complexity in ensemble firing patterns across time. Clustering techniques applied to the full population revealed a large number of distinct categories of task-phase-specific activity patterns. Unique population firing-rate vectors defined each task phase and most categories of task-phase-specific firing had counterparts with opposing firing patterns. An analogous set of task-phase-specific firing patterns was also observed in a population of posterior parietal cortex neurons. Thus, consistent with the known anatomical complexity, basal forebrain population dynamics are capable of differentially modulating their cortical targets according to the unique sets of environmental stimuli, motor requirements, and cognitive processes associated with different task phases

Functional interactions between the hippocampus, medial entorhinal cortex and medial prefrontal cortex for spatial and nonspatial processing

Memory formation and recall depend on a complex circuit that includes the hippocampus and associated cortical regions. The goal of this thesis was to understand how two of the cortical connections, the medial entorhinal cortex (MEC) and medial prefrontal cortex (mPFC), influence spatial and nonspatial activity in the hippocampus. Cells in the MEC exhibit prominent spatially selective activity and have been hypothesized to drive place representation in the hippocampus. In Experiment 1 the MEC was transiently inactivated using the inhibitory opsin ArchaerhodopsinT (ArchT), and simultaneous recordings from CA1 were made as rats ran on an elliptical track. In response to MEC disruption some cells in the hippocampus shifted the preferred location of activity, some changed firing rate and others were unaffected. The new representation that developed following MEC disruption remained stable despite the fact that inhibition was transient. If the MEC is the source of spatial activity in the hippocampus the activity would be either time-locked to periods of inhibition or unstable throughout the period of inconsistent input. These results show that the MEC guides spatial representation in the hippocampus but does not directly drive spatial firing. The mPFC is generally thought to guide behavior in response to contextual elements. Experiment 2 examined the interaction between the mPFC and the hippocampus as rats performed a contextual discrimination task. Recordings were made in CA1, and the mPFC was disrupted using ArchT during the odor sampling phase of the discrimination. As animals perform this task neurons in the hippocampus respond to a conjunction of odor and location which indicates an association of what and where information in the hippocampus. Optogenetic disruption of the mPFC led to a decrease in nonspatial representation. Individual cells showed lower levels of odor selectivity, but there was no change in the level of spatial representation. This indicates that the mPFC is important for determining how the hippocampus represents nonspatial information but does not alter the spatial representation. The results are discussed within a model of memory formation that includes binding spatial and nonspatial information in the hippocampus

Hippocampal output to neocortex: Examination of the electrophysiological and plastic properties of CA1 projections to the perirhinal cortex

The hippocampal formation is an important structure in learning and memory that is required for the transfer of sensory information into long-term storage. This long-term storage is believed to occur in the neocortex and the physiological mechanism underpinning this transfer of information is believed to be long-term changes in synaptic plasticity, namely long-term potentiation (LTP) and depression (LTD). The aim of this thesis is to characterise synaptic plasticity in a particular hippocampal-neocortical projection. The CA1 to perirhinal cortex projection has been previously shown to sustain LTP; by stimulating the area CA1 and recording in the perirhinal cortex, we show that it can sustain short- and long-term changes in synaptic plasticity. Additionally we demonstrate that multiple frequencies of high-frequency stimulation can induce LTP in this projection and that LTP-induction may require AMPA/kainate receptor activation but not NMDA receptor activation; indicating that glutamatergic signalling underlies synaptic plasticity in this projection. We also determine the role of the CA1 to perirhinal cortex projection in a model of electrophysiologically excitatory and inhibitory hippocampal projections to the parahippocampal region of the neocortex. We propose that this projection forms part of an electrophysiologically excitatory circuit from the distal CA1 and proximal subiculum along with the lateral entorhinal cortex. Moreover, we investigate the roles of the hippocampus and perirhinal cortex in recognition and spatial memory. Utilising an object recognition task (a recognition memory task) and an object displacement task (a spatial memory task), we show that there are increased levels of hippocampal brain-derived neurotrophic factor (BDNF) following the spatial task. Furthermore, we demonstrate that AMPA/kainate glutamate receptors are necessary for performance in the object recognition task whereas both NMDA and AMPA/kainate receptors are required for the object displacement task. These findings suggest that glutamatergic signalling not only underlies synaptic plasticity in the CA1 to perirhinal cortex projection but that it is also required for learning and memory in recognition and spatial tasks

Circuit mechanisms for learning in the rodent Prefrontal cortex and their dysfunction in Schizophrenia

Flexible behavior, as shown by most mammals, requires continuous decision making where appropriate actions must be chosen from an array of available actions based on our current goals and prior experience. The medial prefrontal cortex (mPFC) is essential for selecting such appropriate actions and inhibiting inappropriate ones. The prefrontal cortex is not a homogenous structure but rather an agglomeration of sub-areas, which sub serve different functions. For example, the anterior cingulate is required for effort-based decision-making while the orbitofrontal cortex is essential for value based decision-making. However, the outcome of a decision making process is selection of a singular behavioral action or learning a new association. Hence, it would be reasonable to hypothesize that this selection would be a product of the combined output of the various prefrontal areas and the interactions among them. Thus to understand the neurobiological substrates of decision making one needs to explore the prefrontal cortex at two different levels: 1. The internal microcircuit and neuronal networks within individual prefrontal areas, and 2. Functional interactions among the prefrontal areas. The broad goal of my thesis was to use both of these approaches to study the prefrontal cortex of a well-established model organism (mouse) which has a relatively simple behavioral repertoire yet is evolutionarily complex enough to generalize my findings to higher order animals. First, I focused my attention on the Prelimbic (PreL) and Infralimbic (IL) regions of the mouse medial prefrontal cortex (mPFC). These two areas have been studied most extensively among the rodent prefrontal areas. In several behavioral domains, the PreL and IL exert distinct and opposing, influences over behavior; in a PreL-Go/IL-NoGo manner. The most common examples of this complementary function are the expression and extinction of conditioned fear responses or drug seeking behavior. Furthermore, neuronal tuning studies have shown that the PreL neurons are tuned to the representation of goals in goal directed learning while the IL neurons appear to tune to alternative choices. I investigated how the PreL and IL cortices interact among each other to influence learning and selection of behavioral strategies. Such, interactions between IL and PreL or other prefrontal areas have not been studied in detail in the past with one notable exception. Research done by Ji and Neugebauer (2012) have shown that optogenetic activation of IL inhibits PreL pyramidal cells in vivo, implying an existence of feed-forward inhibition from the IL to PreL. I carried out selective chemogenetic silencing of PreL or IL during different sub phases of the Intra-dimension/ extra-dimension set shifting task (IEST) or trace learning and extinction to evaluate their individual contributions. My findings suggest that PreL promotes application of behavioral strategies or new learning corresponding to previously learnt associations while IL is required to learn alternative associations across different learning paradigms. Next, using viral mediated tracing techniques I show the existence of reciprocal layer5/6 derived IL↔PreL projections. Using selective unidirectional silencing/activation of these projections, I have shown that the ILPreL and PreLIL projections are required at different phases of learning. Unidirectional ILPreL projections are specifically required during IL mediated alternative learning (eg: extinction) and the PreL↔IL reciprocal projections are required +12-14h post learning to setup the role of IL in subsequent learning of alternative choices. Prefrontal cortex dysfunction has been identified as a key neurobiological correlate of cognitive deficits associated with many neuropsychiatric disorders like Schizophrenia, Attention deficit/Hyperactivity disorder etc. Exploring the dysfunction of defined prefrontal neuronal networks and circuits in rodent models of neuropsychiatric disorders can be a different approach towards understanding decision making. In the second part of the thesis, I explored the dysfunction in the Parvalbumin (PV) interneuron network in a mouse model of Schizophrenia. Parvalbumin interneurons have been shown to synchronize network activity, supporting different types of neuronal network oscillations, such as gamma and theta oscillation, ripple and spindle activity. Thereby, they play a significant role in the formation and consolidation of memories to support learning and behavior. Finally, dysfunction of the Parvalbumin interneuron system in the prefrontal cortex of human schizophrenia patients has emerged as a core substrate underlying the cognitive deficits in the disease. Thus, studying the dysfunction of the PV network in Schizophrenia not only provides a way to understanding their role in prefrontal function but also raise the possibility of developing a strategy to ameliorate the associated cognitive deficits. I first showed that the PV network in LgDel+/- animals fail to mature with respect to those of their wild type counterparts and remain stuck in an immature state, which is associated with altered neural synchrony in the gamma band and behavioral deficits. I further show that stimulation of the PreL PV neuron network within a specific window of treatment during early adulthood can rescue the dysfunctional PV network synchrony as well as behavioral deficits. In recent years, interactions between the hippocampus and prefrontal cortex (PFC) have emerged as key players in various cognitive and behavioral functions. Disruptions in hippocampal-prefrontal interactions have also been observed in psychiatric disease, most notably schizophrenia. I saw that long-term rescue of the PreL PV state and associated behavioral deficits in LgDel+/- mice can also be mediated through direct stimulation of the ventral hippocampal (vH) PV network. However if the rescue is targeted to PreL while preventing it in vH or vice versa, it fails to mediate any behavioral rescue in LgDel+/- mice. Thus suggesting that long-term rescue of the PV pathology and cognitive deficits in LgDel+/- animals requires a rescue of the entire hippocampal-prefrontal axis