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The structure-guided design of chloride-conducting channelrhodopsins has illuminated mechanisms underlying ion selectivity of this remarkable family of light-activated ion channels. The first generation of chloride-conducting channelrhodopsins, guided in part by development of a structure-informed electrostatic model for pore selectivity, included both the introduction of amino acids with positively charged side chains into the ion conduction pathway and the removal of residues hypothesized to support negatively charged binding sites for cations. Engineered channels indeed became chloride selective, reversing near −65 mV and enabling a new kind of optogenetic inhibition; however, these first-generation chloride-conducting channels displayed small photocurrents and were not tested for optogenetic inhibition of behavior. Here we report the validation and further development of the channelrhodopsin pore model via crystal structure-guided engineering of next-generation light-activated chloride channels (iC++) and a bistable variant (SwiChR++) with net photocurrents increased more than 15-fold under physiological conditions, reversal potential further decreased by another ∼15 mV, inhibition of spiking faithfully tracking chloride gradients and intrinsic cell properties, strong expression in vivo, and the initial microbial opsin channel-inhibitor–based control of freely moving behavior. We further show that inhibition by light-gated chloride channels is mediated mainly by shunting effects, which exert optogenetic control much more efficiently than the hyperpolarization induced by light-activated chloride pumps. The design and functional features of these next-generation chloride-conducting channelrhodopsins provide both chronic and acute timescale tools for reversible optogenetic inhibition, confirm fundamental predictions of the ion selectivity model, and further elucidate electrostatic and steric structure–function relationships of the light-gated pore.

Impaired function in the medial prefrontal cortex (mPFC) contributes to depression, and the therapeutic response produced by novel rapid-acting antidepressants such as ketamine are mediated by mPFC activity. The mPFC contains multiple types of pyramidal cells, but it is unclear whether a particular subtype mediates the rapid antidepressant actions of ketamine. Here we tested two major subtypes, Drd1 and Drd2 dopamine receptor expressing pyramidal neurons and found that activating Drd1 expressing pyramidal cells in the mPFC produces rapid and long-lasting antidepressant and anxiolytic responses. In contrast, photostimulation of Drd2 expressing pyramidal cells was ineffective across anxiety-like and depression-like measures. Disruption of Drd1 activity also blocked the rapid antidepressant effects of ketamine. Finally, we demonstrate that stimulation of mPFC Drd1 terminals in the BLA recapitulates the antidepressant effects of somatic stimulation. These findings aid in understanding the cellular target neurons in the mPFC and the downstream circuitry involved in rapid antidepressant responses. Ketamine exerts fast-acting anti-depressant responses. Here the authors show that dopamine D1 receptor expressing neurons in the medial prefrontal cortex contribute to these antidepressant-like effects in mice.

Background: Electromagnetic field (EMF) exposure is increasingly common and has been implicated in a range of effects on human health. Conditioned fear memory plays a critical role in enabling organisms to respond appropriately to previously encountered threats. Despite growing interest in the neurobiological consequences of EMF exposure, its impact on the neural circuits underlying conditioned fear responses has not been clearly defined. Methods: Using a mouse model exposed to combined microwave and static magnetic fields, we examined the involvement of the primary auditory cortex-basolateral amygdala (Au1-BLA) circuit in EMF-associated alterations in conditioned fear retrieval. A multifaceted experimental approach was employed, including behavioral assays, viral tracing, genetically encoded calcium imaging, chemogenetic modulation, histopathological analysis, and immunofluorescence. Results: Exposure was associated with reduced conditioned fear memory retrieval, pathological changes in Au1 and BLA tissue ultra-structures, and decreased Nissl bodies in Au1 neurons and Au1-BLA neuronal fiber projections. The attenuation of conditioned fear memory retrieval coincided with decreased calcium activity in Au1 and BLA neurons. Consistently, chemogenetic activation of Au1 calcium-dependent protein kinase II (CaMKII)-expressing neurons enhanced calcium activity in BLA neurons during fear retrieval and was accompanied by changes in cholinergic signaling in the BLA. These findings suggest that cholinergic neuronal populations downstream of the Au1-BLA circuit are sensitive to EMF exposure and may participate in EMF-related modulation of fear retrieval. Conclusions: Our findings support an association between EMF exposure and altered conditioned fear expression involving functional changes within the Au1–BLA circuit, especially for the changes in calcium activity and chemogenetic modulation of Au1 CaMKII-expressing neurons. This study provides direct experimental evidence linking EMF exposure to circuit-level functional interactions underlying fear memory retrieval.

Significance Chronic stress has emerged in the epidemiologic literature as a risk factor for both psychiatric and neurodegenerative diseases. Thus, neurologic maladaptation to chronic stress is highly relevant to the pathogenesis of human diseases such as depression and Alzheimer's disease, yet it remains poorly understood. Here we report a study of the neural circuits and molecular pathways that govern the relationship between stress and cognition. We present data demonstrating that behavioral stress impairs cognitive function via activation of a specific direct neural circuit from the basolateral amygdala to the dorsal hippocampus. Moreover, we delineate a molecular mechanism by which behavioral stress is translated to hippocampal dysfunction via a p25/Cdk5 (cyclin-dependent kinase 5)-dependent pathway and epigenetic alterations of neuroplasticity-related gene expression. Repeated stress has been suggested to underlie learning and memory deficits via the basolateral amygdala (BLA) and the hippocampus; however, the functional contribution of BLA inputs to the hippocampus and their molecular repercussions are not well understood. Here we show that repeated stress is accompanied by generation of the Cdk5 (cyclin-dependent kinase 5)-activator p25, up-regulation and phosphorylation of glucocorticoid receptors, increased HDAC2 expression, and reduced expression of memory-related genes in the hippocampus. A combination of optogenetic and pharmacosynthetic approaches shows that BLA activation is both necessary and sufficient for stress-associated molecular changes and memory impairments. Furthermore, we show that this effect relies on direct glutamatergic projections from the BLA to the dorsal hippocampus. Finally, we show that p25 generation is necessary for the stress-induced memory dysfunction. Taken together, our data provide a neural circuit model for stress-induced hippocampal memory deficits through BLA activity-dependent p25 generation.