Optogenetics offers promise for dissecting the complex neural circuits of the spinal cord and peripheral nervous system and has therapeutic potential for addressing unmet clinical needs. Much ...progress has been made to enable optogenetic control in normal and disease states, both in proof-of-concept and mechanistic studies in rodent models. In this Review, we discuss challenges in using optogenetics to study the mammalian spinal cord and peripheral nervous system, synthesize common features that unite the work done thus far, and describe a route forward for the successful application of optogenetics to translational research beyond the brain.
How have complex brains evolved from simple circuits? Here we investigated brain region evolution at cell-type resolution in the cerebellar nuclei, the output structures of the cerebellum. Using ...single-nucleus RNA sequencing in mice, chickens, and humans, as well as STARmap spatial transcriptomic analysis and whole-central nervous system projection tracing, we identified a conserved cell-type set containing two region-specific excitatory neuron classes and three region-invariant inhibitory neuron classes. This set constitutes an archetypal cerebellar nucleus that was repeatedly duplicated to form new regions. The excitatory cell class that preferentially funnels information to lateral frontal cortices in mice becomes predominant in the massively expanded human lateral nucleus. Our data suggest a model of brain region evolution by duplication and divergence of entire cell-type sets.
Collections of cells called engrams are thought to represent memories. Although there has been progress in identifying and manipulating single engrams, little is known about how multiple engrams ...interact to influence memory. In lateral amygdala (LA), neurons with increased excitability during training outcompete their neighbors for allocation to an engram. We examined whether competition based on neuronal excitability also governs the interaction between engrams. Mice received two distinct fear conditioning events separated by different intervals. LA neuron excitability was optogenetically manipulated and revealed a transient competitive process that integrates memories for events occurring closely in time (coallocating overlapping populations of neurons to both engrams) and separates memories for events occurring at distal times (disallocating nonoverlapping populations to each engram).
Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not ...fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state.
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•MultiMAP: registering brain-wide cellular-resolution dynamics with molecular identity•Diverse neuromodulatory cell types across the zebrafish brain correlate with alertness•Neuromodulator-specific brain-state-dependent dynamics are conserved from fish to mouse•Activation of diverse neuromodulators similarly modulates alertness-related behavior
Registration of brain-wide activity measurements with multiple molecular markers at cellular resolution uncovers multiple diverse neuromodulatory pathways linked to brain state.
Everyday function demands efficient and flexible decision-making that allows for habitual and goal-directed action control. An inability to shift has been implicated in disorders with impaired ...decision-making, including obsessive-compulsive disorder and addiction. Despite this, our understanding of the specific molecular mechanisms and circuitry involved in shifting action control remains limited. Here we identify an endogenous molecular mechanism in a specific cortical-striatal pathway that mediates the transition between goal-directed and habitual action strategies. Deletion of cannabinoid type 1 (CB1) receptors from cortical projections originating in the orbital frontal cortex (OFC) prevents mice from shifting from goal-directed to habitual instrumental lever pressing. Activity of OFC neurons projecting to dorsal striatum (OFC-DS) and, specifically, activity of OFC-DS terminals is necessary for goal-directed action control. Lastly, CB1 deletion from OFC-DS neurons prevents the shift from goal-directed to habitual action control. These data suggest that the emergence of habits depends on endocannabinoid-mediated attenuation of a competing circuit controlling goal-directed behaviors.
•OFC-DS circuit mediates goal-directed control of actions•Inhibition of OFC-DS transmission is necessary for habitual action control•Selective deletion of CB1 receptors in OFC-DS neurons prevents habit formation•Endocannabinoid-mediated weakening of goal-directed circuits allows for habit formation
Gremel et al. show an endogenous molecular mechanism in an identified corticostriatal circuit that controls shifts in behavioral control between goal-directed and habitual strategies. Habitual action control necessitates the endocannabinoid-mediated weakening of an orbitostriatal circuit that sustains goal-directed control.
Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) ...within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.
Astrocytes provide structural and metabolic support for neuronal networks, but direct evidence demonstrating their active role in complex behaviors is limited. Central respiratory chemosensitivity is ...an essential mechanism that, via regulation of breathing, maintains constant levels of blood and brain pH and partial pressure of CO₂. We found that astrocytes of the brainstem chemoreceptor areas are highly chemosensitive. They responded to physiological decreases in pH with vigorous elevations in intracellular Ca²⁺ and release of adenosine triphosphate (ATP). ATP propagated astrocytic Ca²⁺ excitation, activated chemoreceptor neurons, and induced adaptive increases in breathing. Mimicking pH-evoked Ca²⁺ responses by means of optogenetic stimulation of astrocytes expressing channelrhodopsin-2 activated chemoreceptor neurons via an ATP-dependent mechanism and triggered robust respiratory responses in vivo. This demonstrates a potentially crucial role for brain glial cells in mediating a fundamental physiological reflex.
A major challenge in understanding the cellular diversity of the brain has been linking activity during behavior with standard cellular typology. For example, it has not been possible to determine ...whether principal neurons in prefrontal cortex active during distinct experiences represent separable cell types, and it is not known whether these differentially active cells exert distinct causal influences on behavior. Here, we develop quantitative hydrogel-based technologies to connect activity in cells reporting on behavioral experience with measures for both brain-wide wiring and molecular phenotype. We find that positive and negative-valence experiences in prefrontal cortex are represented by cell populations that differ in their causal impact on behavior, long-range wiring, and gene expression profiles, with the major discriminant being expression of the adaptation-linked gene NPAS4. These findings illuminate cellular logic of prefrontal cortex information processing and natural adaptive behavior and may point the way to cell-type-specific understanding and treatment of disease-associated states.
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•Cohort-scale CLARITY is enabled for whole-brain activity/projection measurements•mPFC cells active during distinct-valence experiences exhibit distinct projections•Positive-valence experience preferentially recruits an NPAS4+ population in mPFC•Recruiting diverse experience-defined mPFC ensembles drives distinct behaviors
A quantitative analysis of the wiring and molecular properties of neurons in the prefrontal cortex that are associated with distinct behavioral experiences illuminates the logic of information processing in the brain.
Habits tend to form slowly but, once formed, can have great stability. We probed these temporal characteristics of habitual behaviors by intervening optogenetically in forebrain habit circuits as ...rats performed well-ingrained habitual runs in a T-maze. We trained rats to perform a maze habit, confirmed the habitual behavior by devaluation tests, and then, during the maze runs (ca. 3 s), we disrupted population activity in a small region in the medial prefrontal cortex, the infralimbic cortex. In accordance with evidence that this region is necessary for the expression of habits, we found that this cortical disruption blocked habitual behavior. Notably, however, this blockade of habitual performance occurred on line, within an average of three trials (ca. 9 s of inhibition), and as soon as during the first trial (<3 s). During subsequent weeks of training, the rats acquired a new behavioral pattern. When we again imposed the same cortical perturbation, the rats regained the suppressed maze-running that typified the original habit, and, simultaneously, the more recently acquired habit was blocked. These online changes occurred within an average of two trials (ca. 6 s of infralimbic inhibition). Measured changes in generalized performance ability and motivation to consume reward were unaffected. This immediate toggling between breaking old habits and returning to them demonstrates that even semiautomatic behaviors are under cortical control and that this control occurs online, second by second. These temporal characteristics define a framework for uncovering cellular transitions between fixed and flexible behaviors, and corresponding disturbances in pathologies.
Enhanced glutamatergic transmission in the nucleus accumbens (NAc), a region critical for reward and motivation, has been implicated in the pathophysiology of depression; however, the afferent source ...of this increased glutamate tone is not known. The NAc receives glutamatergic inputs from the medial prefrontal cortex (mPFC), ventral hippocampus (vHIP) and basolateral amygdala (AMY). Here, we demonstrate that glutamatergic vHIP afferents to NAc regulate susceptibility to chronic social defeat stress (CSDS). We observe reduced activity in vHIP in mice resilient to CSDS. Furthermore, attenuation of vHIP-NAc transmission by optogenetic induction of long-term depression is pro-resilient, whereas acute enhancement of this input is pro-susceptible. This effect is specific to vHIP afferents to the NAc, as optogenetic stimulation of either mPFC or AMY afferents to the NAc is pro-resilient. These data indicate that vHIP afferents to NAc uniquely regulate susceptibility to CSDS, highlighting an important, novel circuit-specific mechanism in depression.
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