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Emotional responses arise from limbic circuits including the hippocampus and amygdala. In the human brain, beta-frequency communication between these structures correlates with self-reported mood and anxiety. However, both the mechanism and significance of this biomarker as a readout vs. driver of emotional state remain unknown. Here, we show that beta-frequency communication between ventral hippocampus and basolateral amygdala also predicts anxiety-related behavior in mice, both on long timescales (∼30 min) and immediately preceding behavioral choices. Genetically encoded voltage indicators reveal that this biomarker reflects synchronization between somatostatin interneurons across both structures. Indeed, synchrony between these neurons dynamically predicts approach-avoidance decisions, and optogenetically shifting the phase of synchronization by just 25 ms is sufficient to bidirectionally modulate anxiety-related behaviors. Thus, back-translation establishes a human biomarker as a causal determinant (not just predictor) of emotional state, revealing a novel mechanism whereby interregional synchronization that is frequency, phase, and cell type specific controls emotional processing. [Display omitted] • Amygdala-hippocampus (HPC) β-synchrony tracks emotional state in humans and mice • This biomarker reflects synchronization between SST+ neurons in the BLA and HPC • Manipulating BLA-HPC SST+ neuron β-synchrony bidirectionally alters anxiety behavior • BLA-SST+ neurons directly inhibit ventral HPC SST+ interneurons Examining a synchrony-based biomarker for emotional state previously identified in humans, Jackson et al. validate the same biomarker in mice, finding that it depends on amygdala and hippocampus somatostatin neurons, which are linked by direct connections. They show that this biomarker is a causal driver (not just readout) of behavior. [ABSTRACT FROM AUTHOR]

Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene. Syngap+/- and Fmr1-/y mice show increases in basal protein synthesis and metabotropic glutamate receptor (mGluR)-dependent long-term depression that, unlike in their wild-type controls, is independent of new protein synthesis. Basal levels of phosphorylated ERK1/2 are also elevated in Syngap+/- hippocampal slices. Super-resolution microscopy reveals that Syngap+/- and Fmr1-/y mice show nanoscale alterations in dendritic spine morphology that predict an increase in biochemical compartmentalization. Finally, increased basal protein synthesis is rescued by negative regulators of the mGlu subtype 5 receptor and the Ras-ERK1/2 pathway, indicating that therapeutic interventions for fragile X syndrome may benefit patients with SYNGAP1 haploinsufficiency. [ABSTRACT FROM AUTHOR]

Background: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. Methods: This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3−/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3−/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). Results: We observed that, unlike the wildtype, Nlgn3−/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3−/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3−/y than wildtype rats, indicating the functional impact of the increased cellular excitability. Limitations: Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. Conclusions: We describe altered fear responses in Nlgn3−/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD. [ABSTRACT FROM AUTHOR]