Memory and cognition in schizophrenia.

Episodic memory deficits are consistently documented as a core aspect of cognitive dysfunction in schizophrenia patients, present from the onset of the illness and strongly associated with functional disability. Over the past decade, research using approaches from experimental cognitive neuroscience revealed disproportionate episodic memory impairments in schizophrenia (Sz) under high cognitive demand relational encoding conditions and relatively unimpaired performance under item-specific encoding conditions. These specific deficits in component processes of episodic memory reflect impaired activation and connectivity within specific elements of frontal-medial temporal lobe circuits, with a central role for the dorsolateral prefrontal cortex (DLPFC), relatively intact function of ventrolateral prefrontal cortex and variable results in the hippocampus. We propose that memory deficits can be understood within the broader context of cognitive deficits in Sz, where impaired DLPFC-related cognitive control has a broad impact across multiple cognitive domains. The therapeutic implications of these findings are discussed

Hippocampal regulation of encoding and exploration under the influence of contextual reward and anxiety

Hippocampal researchers have recently turned their attention to the computations that may be implemented by the hippocampal circuit (e.g. pattern separation and pattern completion). This focus on the representational and information-processing capabilities of the hippocampus is likely to be important in resolving on-going debates regarding the nature of hippocampal contributions to perception, anxiety and exploration. A first aim of my research was to examine how context representations interact with reward to influence memory for embedded events. In my first experiment, I show that recollection for neutral objects is improved by sharing a context with other rewarding events. To further examine contextual influences on memory, I conducted a second experiment that examined the effect of contextual reward itself on object memory. Additionally, I manipulated the extent to which disambiguation should rely on hippocampal computations, by varying the perceptual similarity between the rewarding and neutral contexts. Improved object memory was only observed when the rewarding and neutral contexts were perceptually similar, and this contextual memory effect was further linked to co-activation of the hippocampal CA3/dentate gyrus and substantia nigra/ventral tegmental area. A second major aim of my work was to characterize hippocampal contributions to anxiety. In my third experiment, I combine a novel experiment with fMRI to show that hippocampal activation is associated with behavioural inhibition rather than exploratory risk assessment. This insight is important because a major theoretical perspective in the literature conflates these two psychological processes. In my final experiment, I employ this novel experimental paradigm to examine the effect of exploration on memory, and find that the propensity to explore (rather than the act of exploring per se) leads to better memory at subsequent recall

Context-specific activation of hippocampus and SN/VTA by reward is related to enhanced long-term memory for embedded objects

Animal studies indicate that hippocampal representations of environmental context modulate reward-related processing in the substantia nigra and ventral tegmental area (SN/VTA), a major origin of dopamine in the brain. Using functional magnetic resonance imaging (fMRI) in humans, we investigated the neural specificity of context-reward associations under conditions where the presence of perceptually similar neutral contexts imposed high demands on a putative hippocampal function, pattern separation. The design also allowed us to investigate how contextual reward enhances long-term memory for embedded neutral objects. SN/VTA activity underpinned specific context-reward associations in the face of perceptual similarity. A reward-related enhancement of long-term memory was restricted to the condition where the rewarding and the neutral contexts were perceptually similar, and in turn was linked to co-activation of the hippocampus (subfield DG/CA3) and SN/VTA. Thus, an ability of contextual reward to enhance memory for focal objects is closely linked to context-related engagement of hippocampal-SN/VTA circuitry

Individual Differences in Memory Functions and Their Relation to Hippocampal Connectivity

The hippocampus plays an important role in many aspects of learning and memory. It is most known for its role in episodic memory and spatial navigation, though it has also been shown to contribute to other processes like prioritizing memory for motivationally salient information and connecting related memories to form generalized knowledge. How can a single structure support different types of learning? As the hippocampus does not work in isolation to support memory, one proposal is that it may form connections with different brain regions to support different functions of memory. Recent work has shown how stable, trait-like connections can be leveraged to predict individual behavior. Thus, the present dissertation aims to explore 1) how different hippocampal connections relate to different memory processes, and 2) whether intrinsic hippocampal connections can be linked to individual memory performance. In three empirical chapters, I demonstrate how distinct hippocampal connections are associated with different functions of memory, including reward motivated learning, generalization and memory specificity. Moreover, I show how anterior and posterior hippocampus form distinct connections that may further support different aspects of memory. Finally, the dissertation demonstrates how stable, trait-like hippocampal connections can be linked to individual behavior. Together, these findings provide insight into the different functions of hippocampal connectivity and the utility of intrinsic connections in understanding individual memory abilities

Content representation in the human medial temporal lobe

The transformation of sensory inputs into complex memory representations is fundamental to human experience; yet, little is known about how this crucial process is achieved. When you meet your friend at the new cafe in town, what part of the brain encodes this novel scene into long term memory? What part encoded your friend’s favorite t-shirt, so that the sight of it gives you a feeling of familiarity rather than surprise? It is well-established that the medial temporal lobe (MTL) is crucial to both processes, but the MTL is not a single homogeneous region. In fact, it is composed of several anatomically distinct subregions including hippocampus, perirhinal cortex (PRC) and parahippocampal cortex (PHC). However, the computations performed by each subregion to encode individual events is still unclear. The present research tests the central hypothesis that different forms of event content are transformed into memory by distinct subregions within the MTL. A critical barrier in the study of content representation thus far has been its focus on comparing univariate peak activations in a region to different stimulus materials. To go beyond this limited approach, we employed multivariate statistical analyses that takes into account how event content is represented by distributed activity in MTL subregions. First, we examine the content-specific contributions of MTL subregions to episodic encoding and retrieval. Then, we demonstrate how these distributed representations support memory-based prediction to resolve ambiguities in our environment.Neuroscienc

Two photon interrogation of hippocampal subregions CA1 and CA3 during spatial behaviour

The hippocampus is crucial for spatial navigation and episodic memory formation. Hippocampal place cells exhibit spatially selective activity within an environment and form the neural basis of a cognitive map of space which supports these mnemonic functions. Hebb’s (1949) postulate regarding the creation of cell assemblies is seen as the pre-eminent model of learning in neural systems. Investigating changes to the hippocampal representation of space during an animal’s exploration of its environment provides an opportunity to observe Hebbian learning at the population and single cell level. When exploring new environments animals form spatial memories that are updated with experience and retrieved upon re-exposure to the same environment, but how this is achieved by different subnetworks in hippocampal CA1 and CA3, and how these circuits encode distinct memories of similar objects and events remains unclear. To test these ideas, we developed an experimental strategy and detailed protocols for simultaneously recording from CA1 and CA3 populations with 2P imaging. We also developed a novel all-optical protocol to simultaneously activate and record from ensembles of CA3 neurons. We used these approaches to show that targeted activation of CA3 neurons results in an increasing excitatory amplification seen only in CA3 cells when stimulating other CA3 cells, and not in CA1, perhaps reflecting the greater number of recurrent connections in CA3. To probe hippocampal spatial representations, we titrated input to the network by morphing VR environments during spatial navigation to assess the local CA3 as well as downstream CA1 responses. To this end, we found CA1 and CA3 neural population responses behave nonlinearly, consistent with attractor dynamics associated with the two stored representations. We interpret our findings as supporting classic theories of Hebbian learning and as the beginning of uncovering the relationship between hippocampal neural circuit activity and the computations implemented by their dynamics. Establishing this relationship is paramount to demystifying the neural underpinnings of cognition

States of curiosity modulate hippocampus-dependent learning via the dopaminergic circuit

People find it easier to learn about topics that interest them, but little is known about the mechanisms by which intrinsic motivational states affect learning. We used functional magnetic resonance imaging to investigate how curiosity (intrinsic motivation to learn) influences memory. In both immediate and one-day-delayed memory tests, participants showed improved memory for information that they were curious about and for incidental material learned during states of high curiosity. Functional magnetic resonance imaging results revealed that activity in the midbrain and the nucleus accumbens was enhanced during states of high curiosity. Importantly, individual variability in curiosity-driven memory benefits for incidental material was supported by anticipatory activity in the midbrain and hippocampus and by functional connectivity between these regions. These findings suggest a link between the mechanisms supporting extrinsic reward motivation and intrinsic curiosity and highlight the importance of stimulating curiosity to create more effective learning experiences