Probing the neural circuit basis of normal and disease-relevant cognitive function in mice

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Cognitive processes like working memory manifest out of orchestrated communication across expansive brain networks. The medial prefrontal cortex (mPFC) functions as a critical hub in these networks, wherein task-relevant information is dynamically gated and integrated to guide activity in distal brain regions and support contextually tuned behavior. mPFC dysfunction is central to many theories of schizophrenia pathogenesis and correlates with cognitive deficits of the disorder. Research further supports that schizophrenia-associated cognitive deficits stem from broad patterns of aberrant neural synchrony and long-range circuit dysconnectivity. However, the neural computations that give rise to normal and disordered cognition, and the micro- and macro-circuits of neurons that subserve these computations, are largely unknown. The Integrative Neuroscience Section uses experimental mice to study the neural circuit basis of cognitive functions such as spatial working memory and their dysfunction in models of genetic susceptibility to schizophrenia and related disorders. Three hypotheses guide much of our research: (1) the structural and functional connectivity of the ventral hippocampus (vHPC) and mPFC is necessary for working memory; (2) inhibitory mPFC microcircuits are essential for this long-range connectivity; and (3) rescuing structural and functional dysconnectivity of the vHPC-mPFC pathway in models of genetic predisposition to schizophrenia stands to rescue working memory deficits. In our lab's fourth year, we have made important technical and experimental progress towards testing these hypotheses. Over the last year, we have refined our lab's capacity for conducting high-fidelity electrical recordings from multiple brain regions in freely behaving mice. We have optimized electrode construction/implantation and pipelines for electrophysiological data analysis. We have diversified our mouse colony to include unique multi-transgenic strains. We have refined our use of optogenetic tools to manipulate the neuronal function during electrophysiological recordings in freely behaving mice. We have also established use of other modern tools of circuit neuroscience, including simultaneous in vivo photometry and optogenetic manipulations of discrete cell and circuit functions during behavior. We are applying these and other tools to experimentally address our section aims. One series of experiments is probing the causal role of neural synchrony in vHPC-mPFC circuits in cognitive function. We know that activity in discrete neural projections from vHPC to mPFC is necessary for frequency-specific inter-regional synchrony and normal working memory performance. We are using optogenetics to promote or disrupt oscillatory synchrony in real time to modulate working memory performance. More specifically, we are manipulating activity of vHPC projections to the mPFC in a closed-loop manner informed by ongoing vHPC activity patterns with the goal of promoting neuronal communication between these structures and enhancing spatial working memory performance. By systematically varying the frequency, intensity and phase of the optical manipulation in relation to ongoing vHPC activity, we have revealed complex sensitivities of the vHPC-mPFC physiological response to specific features of our manipulations. These sensitivities inform our current efforts to influence performance of wildtype mice in a test of spatial working memory. Once refined, we will apply our closed-loop manipulations in mice harboring genetic alterations that confer significant risk for developing cognitive deficits and psychiatric illness in humans (e.g. Df(16)A+/- model of the 22q11.2 microdeletion syndrome). We have also used behavioral methods to induce plasticity in the vHPC-mPFC system. Specifically, in collaboration with laboratories at Columbia University, we found that priming with exposure to a novel environment facilitates flexible learning of a working memory task. The effects of novelty are mediated by a dopaminergic activation of mPFC-projecting vHPC neurons which subsequently induces potentiation of vHPC-mPFC synaptic efficacy. We have also published three additional manuscripts that represent the culmination of several long-standing collaborations aimed at elucidating the role of the mPFC, vHPC, and other related structures in emotional and cognitive behaviors. Similar to vHPC-mPFC projections, neural activity in discrete mPFC interneuron populations (e.g. somatostatin-positive SST+) is essential for normal vHPC-mPFC communication and spatial working memory. Furthermore, like vHPC-mPFC projections, alterations in interneuron function may also underlie cognitive and synchrony deficits in schizophrenia-relevant mouse models. Thus, we analyzed interneuron population activity dynamics in mice as they performed in a spatial working memory task. Using fiber photometry, we found that SST+ and parvalbumin-postiive (PV+) interneuron populations are differentially engaged during phases of the task that relate to the encoding and retrieval of task-relevant spatial information. Ongoing work is exploring whether optogenetic activation of different interneuron populations in discrete phases of the T-maze task can influence performance by wildtype and Df(16)A+/- mice. We are also examining how vHPC inputs functionally interact with mPFC interneurons in vivo, and how these interactions may be altered to promote vHPC-mPFC connectivity. To do so, we combined optogenetic stimulation of vHPC-mPFC projections with fiber photometry to monitor activity in discrete mPFC interneuron populations in behaving mice. We found that stimulation-evoked SST+ interneuron responses in Df(16)A+/- mice were weaker than those in wildtype mice. We further showed that repeated daily high-frequency stimulation of vHPC inputs to mPFC increased evoked SST+ interneuron responses in both genotypes. Stimulation in Df(16)A+/- mice potentiated SST+ interneuron responses to levels observed in WT mice without such stimulation. Ongoing work in our lab and in collaboration with colleagues at NIDA is exploring potential structural bases of these functional data. Future work will assess how this plasticity influences spatial working memory performance. We are also exploring pharmacological approaches to rescue cognitive deficits in mouse models relevant to schizophrenia. We found that administration of a selective GSK3-beta inhibitor in early postnatal development rescues deficits in working memory task learning in adult male but not female Df(16)A+/- mice. We further found that selective GSK3-beta inhibition rescues deficits in theta frequency (4-12 Hz) synchrony between vHPC and mPFC, a neurophysiological correlate of spatial working memory performance, in Df(16)A+/- mice. In contrast, selective postnatal GSK3-alpha inhibition rescues deficits in working memory performance under conditions of increased memory demands in both male and female Df(16)A+/- mice but has no significant effect on task acquisition. Ongoing transcriptomic analysis of the mPFC and vHPC of wildtype and Df(16)A+/- mice at various developmental stages will help inform the molecular basis of our behavioral and neurophysiological findings. Finally, we are characterizing potential sex-specific changes in vHPC-mPFC-thalamic neurophysiology and cognitive performance in mice haploinsufficient for SETD1A, a gene whose loss-of-function in humans confers significant additional schizophrenia risk. Despite showing intact spatial working memory performance, male and female Setd1a+/- mice display significantly lower theta-frequency synchrony between the mPFC and nucleus reuniens, a region implicated in spatial working memory. Preliminary work also suggests that relative to wildtype mice, male Setd1a+/- mice show improved accuracy in a task of spatial attenti