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

National Institute Of Neurological Disorders And Stroke

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Abstract

In the final year of the Integrative Neuroscience Section, we prioritized experiments required to complete several ongoing projects. These projects span three key domains: 1. Oscillatory synchrony and SWM in mouse models relevant to psychiatric disease. Dysregulated GSK3 signaling is linked to schizophrenia and other psychiatric disorders. We previously showed that early-life treatment with a nonselective GSK3 (alpha and beta isoform) inhibitor rescues deficits in SWM task acquisition and vHPC-mPFC synchrony in adult male Df(16)A+/- mice. Considering isoform-specific and sex-divergent GSK3 signaling, we tested the effects of selective GSK3-alpha and beta inhibitors on SWM and vHPC-mPFC synchrony in male and female wildtype (WT) and Df(16)A+/- mice. GSK3-beta inhibition from P7-P28 improved SWM task acquisition in adult male but not female Df(16)A+/- mice, and modulated task-related vHPC-mPFC theta coherence and mPFC neuronal spiking. Conversely, GSK3-alpha inhibition didn’t improve task acquisition but enhanced task performance under higher SWM demand in Df(16)A+/- mice of both sexes. RNA sequencing of mPFC and vHPC tissue revealed sex-, genotype- and age-specific transcriptomic profiles underlying our behavioral and neurophysiological findings. Heterozygous null mutations of SETD1A are associated with increased risk for schizophrenia. Mice with similar mutations reportedly show SWM deficits. We investigated synchrony between the mPFC, vHPC, dorsal hippocampus, and nucleus reuniens (Re) of the thalamus in male and female mice during a SWM task. Setd1a+/- mice showed a modest SWM deficit relative to WT controls under conditions of low SWM load. Neural recordings indicated Setd1a+/- mice had reduced Re-mPFC beta (13-30 Hz) synchrony compared to WT mice. Moreover, Re-mPFC beta synchrony was modulated across task epochs in WT mice. Specifically, Re-mPFC beta synchrony was enhanced in the beta and reduced in the low gamma (40-50 Hz) frequency ranges in the delay relative to the sample and choice epochs. These task-related Re-mPFC synchrony dynamics were blunted in Setd1a+/- mice relative to WT controls. These findings implicate disruptions in thalamo-prefrontal synchrony and its dynamics in SETD1A-related genetic predisposition to schizophrenia. 2. vHPC-mPFC microcircuit interactions and plasticity. Inhibitory interneurons (INs) in mPFC regulate pyramidal neuron firing, coordinate neural ensembles, and integrate long-range neural input to support SWM. Vasoactive intestinal polypeptide-expressing INs (VIP-INs) have been shown to support mPFC neuronal coding of spatial information during periods of high HC-mPFC oscillatory synchrony. Yet, the circuit mechanisms by which VIP-INs contribute to HC-mPFC synchrony and SWM task-relevant neural coding remain unclear. We sought to characterize the contributions of VIP-INs to HC-mPFC synchrony, task-relevant coding, and SWM performance. Work to date pairing optogenetic manipulations with in vivo electrophysiology has revealed no clear effect of VIP-IN inhibition on SWM performance or vHPC-mPFC synchrony. Ongoing efforts are validating the efficacy of the optogenetic inhibition, including assessing how the inhibition influenced the activity of optically identified VIP-INs. Inhibition of mouse vHPC inputs to mPFC or select mPFC interneuron (IN) populations impairs SWM performance and vHPC-mPFC functional interactions, and plasticity in the vHPC-mPFC circuit has been linked with SWM task learning. Thus, interactions between vHPC inputs and mPFC INs, and their plasticity, may exert unique control over SWM. We combined optogenetic stimulation of vHPC inputs and photometry of mPFC interneuron populations to assess how vHPC inputs interact with mPFC INs in vivo, whether these interactions are plastic, and how altering these interactions influences SWM and related physiology. We found that repeated vHPC input stimulation potentiated mPFC somatostatin-expressing IN responses and depressed vasoactive intestinal peptide (VIP) IN responses. Using whole cell electrophysiology, we found evidence that these population-level changes may be secondary to blunted monosynaptic vHPC input drive of VIP INs. We further showed that delay-related VIP IN activity increases across SWM task training, that prior vHPC input stimulation enhances delay epoch VIP-IN activity in early SWM task training, and that delay epoch VIP-IN activity in early training correlates with less effective SWM task learning. The Df(16)A+/- mouse model with impaired SWM task learning showed reduced vHPC synaptic targeting of VIP INs and displayed heightened delay epoch VIP-IN activity in early training. Together, these findings reveal novel cell-type-specific plasticity in cognition-supporting circuits and illustrate how reweighting of inputs to VIP interneurons may contribute to working memory dysfunction. 3. Real-time modulation of cognition-relevant oscillatory synchrony. Dynamic changes in vHPC-mPFC synchrony correlate with various behaviors, but the causal contributions of such synchrony to behavior is unclear. A robust test of the causal contributions of long-range synchrony to cognitive function might involve the modulating endogenous task-relevant oscillatory activity in real-time in behaving animals. To this end, we created a closed-loop optogenetic stimulation method, activating vHPC projections to mPFC based on ongoing vHPC theta-frequency oscillations. We expressed ChR2 or GFP in vHPC-mPFC terminals in WT mice and governed laser output in the mPFC by the theta-filtered vHPC LFP, allowing for phase delays relative to ongoing vHPC theta oscillations. Near-synchronous stimulation with vHPC theta increased vHPC-mPFC theta coherence in ChR2 mice, less so with greater phase delays. We applied this approach in mice performing a SWM task, hypothesizing that “in-phase” stimulation will enhance SWM performance, and that phase-shifted stimulation will impair it. Neither in-phase nor phase-shifted stimulation affected overall SWM performance. However, in-phase stimulation did preferentially enhance both mPFC theta entrainment and vHPC-mPFC theta coherence. In ChR2 mice, increases in high-theta coherence were negatively changes in DNMS performance. These findings suggest that while CLS can reshape mPFC oscillations and vHPC-mPFC coherence to favor theta frequencies, excessive enhancement of vHPC–mPFC theta coupling may impair SWM performance, pointing to an optimal range of interregional synchrony for successful memory-guided behavior.