A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward.

Nociceptin and its receptor are widely distributed throughout the brain in regions associated with reward behavior, yet how and when they act is unknown. Here, we dissected the role of a nociceptin peptide circuit in reward seeking. We generated a prepronociceptin (Pnoc)-Cre mouse line that revealed a unique subpopulation of paranigral ventral tegmental area (pnVTA) neurons enriched in prepronociceptin. Fiber photometry recordings during progressive ratio operant behavior revealed pnVTAPnoc neurons become most active when mice stop seeking natural rewards. Selective pnVTAPnoc neuron ablation, inhibition, and conditional VTA nociceptin receptor (NOPR) deletion increased operant responding, revealing that the pnVTAPnoc nucleus and VTA NOPR signaling are necessary for regulating reward motivation. Additionally, optogenetic and chemogenetic activation of this pnVTAPnoc nucleus caused avoidance and decreased motivation for rewards. These findings provide insight into neuromodulatory circuits that regulate motivated behaviors through identification of a previously unknown neuropeptide-containing pnVTA nucleus that limits motivation for rewards.

Social Isolation Co-opts Fear and Aggression Circuits.

Social isolation is a stressful condition that often leads to maladaptive behaviors. In this issue of Cell, Zelikowsky et al. find that chronic social isolation stress triggers an increase in neuronal tachykinin signaling across distinct brain regions that mediate fear and aggression, elucidating the neural basis of these maladaptive responses.

Multimodal Signal Integration for Feeding Control.

Feeding is arguably one of the most well-conserved and important adaptive behaviors across all species. In this issue of Cell, Yapici et al. use a novel real-time feeding assay in Drosophila flies to identify a neural circuit that integrates gustatory input and hunger state to modulate food ingestion.

Cell-Type-Specific Optogenetics in Monkeys.

The recent advent of technologies enabling cell-type-specific recording and manipulation of neuronal activity spurred tremendous progress in neuroscience. However, they have been largely limited to mice, which lack the richness in behavior of primates. Stauffer et al. now present a generalizable method for achieving cell-type specificity in monkeys.

Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors.

Optimally orchestrating complex behavioral states, such as the pursuit and consumption of food, is critical for an organism's survival. The lateral hypothalamus (LH) is a neuroanatomical region essential for appetitive and consummatory behaviors, but whether individual neurons within the LH differentially contribute to these interconnected processes is unknown. Here, we show that selective optogenetic stimulation of a molecularly defined subset of LH GABAergic (Vgat-expressing) neurons enhances both appetitive and consummatory behaviors, whereas genetic ablation of these neurons reduced these phenotypes. Furthermore, this targeted LH subpopulation is distinct from cells containing the feeding-related neuropeptides, melanin-concentrating hormone (MCH), and orexin (Orx). Employing in vivo calcium imaging in freely behaving mice to record activity dynamics from hundreds of cells, we identified individual LH GABAergic neurons that preferentially encode aspects of either appetitive or consummatory behaviors, but rarely both. These tightly regulated, yet highly intertwined, behavioral processes are thus dissociable at the cellular level.

An endogenous opioid circuit determines state-dependent reward consumption.

µ-Opioid peptide receptor (MOPR) stimulation alters respiration, analgesia and reward behaviour, and can induce substance abuse and overdose1-3. Despite its evident importance, the endogenous mechanisms for MOPR regulation of consummatory behaviour have remained unknown4. Here we report that endogenous MOPR regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine consummatory response, while select enkephalin-containing nucleus accumbens ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of the endogenous MOPR ligand. Selective modulation of nucleus accumbens enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent consumptive behaviour and suggest alternative mechanisms for opiate modulation of reward.

Gene expression changes following chronic antipsychotic exposure in single cells from mouse striatum.

Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell transcriptomics, and pharmacological studies suggest an important, but untested, overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics. To directly compare genes with antipsychotic-induced differential expression to genes involved in schizophrenia, we applied single-cell RNA-sequencing to striatal samples from male C57BL/6 J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We identified differentially expressed genes in three cell populations identified from the single-cell RNA-sequencing (medium spiny neurons [MSNs], microglia, and astrocytes) and applied multiple analysis pipelines to contextualize these findings, including comparison to GWAS results for schizophrenia. In MSNs in particular, differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) from mice treated with olanzapine compared with haloperidol. DEGs were enriched in loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses of gene expression in MSNs highlighted neuron/synapse development, alternative splicing, and mitochondrial function as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. In conclusion, single-cell RNA sequencing may provide important insights into antipsychotic mechanisms of action and links to findings from psychiatric genomic studies.

Prefrontal cortex output circuits guide reward seeking through divergent cue encoding.

The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species. In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus. While connectivity among these structures contributes to appetitive behaviours, how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations.

Cue and Reward Evoked Dopamine Activity Is Necessary for Maintaining Learned Pavlovian Associations.

Associating natural rewards with predictive environmental cues is crucial for survival. Dopamine (DA) neurons of the ventral tegmental area (VTA) are thought to play a crucial role in this process by encoding reward prediction errors (RPEs) that have been hypothesized to play a role in associative learning. However, it is unclear whether this signal is still necessary after animals have acquired a cue-reward association. In order to investigate this, we trained mice to learn a Pavlovian cue-reward association. After learning, mice show robust anticipatory and consummatory licking behavior. As expected, calcium activity of VTA DA neurons goes up for cue presentation as well as reward delivery. Optogenetic inhibition during the moment of reward delivery disrupts learned behavior, even in the continued presence of reward. This effect is more pronounced over trials and persists on the next training day. Moreover, outside of the task licking behavior and locomotion are unaffected. Similarly to inhibitions during the reward period, we find that inhibiting cue-induced dopamine (DA) signals robustly decreases learned licking behavior, indicating that cue-related DA signals are a potent driver for learned behavior. Overall, we show that inhibition of either of these DA signals directly impairs the expression of learned associative behavior. Thus, continued DA signaling in a learned state is necessary for consolidating Pavlovian associations.SIGNIFICANCE STATEMENT Dopamine (DA) neurons of the ventral tegmental area (VTA) have long been suggested to be necessary for animals to associate environmental cues with rewards that they predict. Here, we use time-locked optogenetic inhibition of these neurons to show that the activity of these neurons is directly necessary for performance on a Pavlovian conditioning task, without affecting locomotor per se These findings provide further support for the direct importance of second-by-second DA neuron activity in associative learning.

Social Stimuli Induce Activation of Oxytocin Neurons Within the Paraventricular Nucleus of the Hypothalamus to Promote Social Behavior in Male Mice.

Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism, Shank3b knock-out (KO) mice. Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number and administration of an OT receptor agonist improved social deficits. Overall, these data suggest that the presence of a social stimulus induces activation of the PVH-OT neurons to promote adaptive social behavior responses.SIGNIFICANCE STATEMENT Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood. One hypothesis is that the presence of social conspecifics activates the OT system to generate an adaptive social response. Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system. We also show that activation of the OT system is necessary to promote social behavior and that mice with abnormal social behavior have reduced numbers of PVH-OT neurons. Finally, aberrant social behavior in these mice was rescued by administration of an OT receptor agonist.

Manipulations of Central Amygdala Neurotensin Neurons Alter the Consumption of Ethanol and Sweet Fluids in Mice.

The central nucleus of the amygdala plays a significant role in alcohol use and other affective disorders; however, the genetically-defined neuronal subtypes and projections that govern these behaviors are not well known. Here we show that neurotensin neurons in the central nucleus of the amygdala of male mice are activated by in vivo ethanol consumption and that genetic ablation of these neurons decreases ethanol consumption and preference in non-ethanol-dependent animals. This ablation did not impact preference for sucrose, saccharin, or quinine. We found that the most robust projection of the central amygdala neurotensin neurons was to the parabrachial nucleus, a brain region known to be important in feeding behaviors, conditioned taste aversion, and alarm. Optogenetic stimulation of projections from these neurons to the parabrachial nucleus is reinforcing, and increases ethanol drinking as well as consumption of sucrose and saccharin solutions. These data suggest that this central amygdala to parabrachial nucleus projection influences the expression of reward-related phenotypes and is a novel circuit promoting consumption of ethanol and palatable fluids.SIGNIFICANCE STATEMENT Alcohol use disorder (AUD) is a major health burden worldwide. Although ethanol consumption is required for the development of AUD, much remains unknown regarding the underlying neural circuits that govern initial ethanol intake. Here we show that ablation of a population of neurotensin-expressing neurons in the central amygdala decreases intake of and preference for ethanol in non-dependent animals, whereas the projection of these neurons to the parabrachial nucleus promotes consumption of ethanol as well as other palatable fluids.

Amygdala Arginine Vasopressin Modulates Chronic Ethanol Withdrawal Anxiety-Like Behavior in the Social Interaction Task.

BACKGROUND: Chronic ethanol (EtOH) exposure induces neurobehavioral maladaptations in the brain though the precise changes have not been fully explored. The central nucleus of the amygdala (CEA) regulates anxiety-like behavior induced by withdrawal from chronic intermittent EtOH (CIE) exposure, and the arginine vasopressin (AVP) system within the CEA regulates many anxiety-like behaviors. Thus, adaptations occur in the CEA AVP system due to chronic EtOH exposure, which lead to anxiety-like behaviors in rats. METHODS: Chronic exposure to a low-dose EtOH (4.5% wt/vol) induces anxiety-like behavior in rats. Wistar or Sprague Dawley rats were exposed to a modified CIE or CIE, while intra-CEA microinjections of AVP or a V1b receptor antagonist were used to elicit or block withdrawal-induced anxiety. Additionally, AVP microinjections into the CEA were given 24 hours following 15 days of continuous high-dose EtOH (7% wt/vol), a time period when rats no longer express anxiety. Chemogenetics was also used to activate the basolateral amygdala (BLA) or deactivate the dorsal periaqueductal gray=(dm/dlPAG) therefore PAG=periaqueductal gray to elicit or block withdrawal-induced anxiety. RESULTS: AVP microinjected into the CEA in lieu of exposure to the first 2 cycles of CIE was sufficient to induce anxiety-like behavior in these commonly used rat strains. The V1b receptor antagonist, but not an oxytocin receptor agonist, into the CEA during the first 2 withdrawal cycles suppressed anxiety. However, activation of the BLA in lieu of exposure to the first 2 cycles of CIE was insufficient to induce anxiety-like behavior. AVP microinjection into the CEA 24 hours into withdrawal reelicited anxiety-like behavior, and deactivation of the dm/dlPAG reduced this effect of CEA AVP. CONCLUSIONS: Taken together, this study demonstrates a role of CEA AVP and a CEA-dm/dlPAG circuit in the development of anxiety induced by CIE. Such information is valuable for identifying novel therapeutic targets for alcohol- and anxiety-associated disorders.

Distinct extended amygdala circuits for divergent motivational states.

The co-morbidity of anxiety and dysfunctional reward processing in illnesses such as addiction and depression suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety, but also projects to the ventral tegmental area (VTA), a region implicated in reward and aversion, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states, have not been described. Here we record and manipulate the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. By contrast, in vivo optically identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic (γ-aminobutyric acid-containing) projection neurons was suppressed. Channelrhodopsin-2-assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioural phenotypes. Conversely, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states, and may serve as a crucial circuit node for bidirectionally normalizing maladaptive behaviours.

Physiological state gates acquisition and expression of mesolimbic reward prediction signals.

Phasic dopamine signaling participates in associative learning by reinforcing associations between outcomes (unconditioned stimulus; US) and their predictors (conditioned stimulus; CS). However, prior work has always engendered these associations with innately rewarding stimuli. Thus, whether dopamine neurons can acquire prediction signals in the absence of appetitive experience and update them when the value of the outcome changes remains unknown. Here, we used sodium depletion to reversibly manipulate the appetitive value of a hypertonic sodium solution while measuring phasic dopamine signaling in rat nucleus accumbens. Dopamine responses to the NaCl US following sodium depletion updated independent of prior experience. In contrast, prediction signals were only acquired through extensive experience with a US that had positive affective value. Once learned, dopamine prediction signals were flexibly expressed in a state-dependent manner. Our results reveal striking differences with respect to how physiological state shapes dopamine signals evoked by outcomes and their predictors.

ERK/MAPK Signaling Is Required for Pathway-Specific Striatal Motor Functions.

The ERK/MAPK intracellular signaling pathway is hypothesized to be a key regulator of striatal activity via modulation of synaptic plasticity and gene transcription. However, prior investigations into striatal ERK/MAPK functions have yielded conflicting results. Further, these studies have not delineated the cell-type-specific roles of ERK/MAPK signaling due to the reliance on globally administered pharmacological ERK/MAPK inhibitors and the use of genetic models that only partially reduce total ERK/MAPK activity. Here, we generated mouse models in which ERK/MAPK signaling was completely abolished in each of the two distinct classes of medium spiny neurons (MSNs). ERK/MAPK deletion in D1R-MSNs (direct pathway) resulted in decreased locomotor behavior, reduced weight gain, and early postnatal lethality. In contrast, loss of ERK/MAPK signaling in D2R-MSNs (indirect pathway) resulted in a profound hyperlocomotor phenotype. ERK/MAPK-deficient D2R-MSNs exhibited a significant reduction in dendritic spine density, markedly suppressed electrical excitability, and suppression of activity-associated gene expression even after pharmacological stimulation. Our results demonstrate the importance of ERK/MAPK signaling in governing the motor functions of the striatal direct and indirect pathways. Our data further show a critical role for ERK in maintaining the excitability and plasticity of D2R-MSNs.SIGNIFICANCE STATEMENT Alterations in ERK/MAPK activity are associated with drug abuse, as well as neuropsychiatric and movement disorders. However, genetic evidence defining the functions of ERK/MAPK signaling in striatum-related neurophysiology and behavior is lacking. We show that loss of ERK/MAPK signaling leads to pathway-specific alterations in motor function, reduced neuronal excitability, and the inability of medium spiny neurons to regulate activity-induced gene expression. Our results underscore the potential importance of the ERK/MAPK pathway in human movement disorders.

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward.

The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neurons, and their projections to the lateral habenula (LHb), negatively regulate the consumption of palatable food. Genetic ablation of LHA glutamatergic neurons increased daily caloric intake and produced weight gain in mice that had access to a high-fat diet, while not altering general locomotor activity. Anterior LHA glutamatergic neurons send a functional glutamatergic projection to the LHb, a brain region involved in processing aversive stimuli and negative reward prediction outcomes. Pathway-specific, optogenetic stimulation of glutamatergic LHA-LHb circuit resulted in detectable glutamate-mediated EPSCs as well as GABA-mediated IPSCs, although the net effect of neurotransmitter release was to increase the firing of most LHb neurons. In vivo optogenetic inhibition of LHA-LHb glutamatergic fibers produced a real-time place preference, whereas optogenetic stimulation of LHA-LHb glutamatergic fibers had the opposite effect. Furthermore, optogenetic inhibition of LHA-LHb glutamatergic fibers acutely increased the consumption of a palatable liquid caloric reward. Collectively, these results demonstrate that LHA glutamatergic neurons are well situated to bidirectionally regulate feeding and potentially other behavioral states via their functional circuit connectivity with the LHb and potentially other brain regions. SIGNIFICANCE STATEMENT: In this study, we show that the genetic ablation of LHA glutamatergic neurons enhances caloric intake. Some of these LHA glutamatergic neurons project to the lateral habenula, a brain area important for generating behavioral avoidance. Optogenetic stimulation of this circuit has net excitatory effects on postsynaptic LHb neurons. This is the first study to characterize the functional connectivity and behavioral relevance of this circuit within the context of feeding and reward-related behavior.

Functional circuit mapping of striatal output nuclei using simultaneous deep brain stimulation and fMRI.

The substantia nigra pars reticulata (SNr) and external globus pallidus (GPe) constitute the two major output targets of the rodent striatum. Both the SNr and GPe converge upon thalamic relay nuclei (directly or indirectly, respectively), and are traditionally modeled as functionally antagonistic relay inputs. However, recent anatomical and functional studies have identified unanticipated circuit connectivity in both the SNr and GPe, demonstrating their potential as far more than relay nuclei. In the present study, we employed simultaneous deep brain stimulation and functional magnetic resonance imaging (DBS-fMRI) with cerebral blood volume (CBV) measurements to functionally and unbiasedly map the circuit- and network level connectivity of the SNr and GPe. Sprague-Dawley rats were implanted with a custom-made MR-compatible stimulating electrode in the right SNr (n=6) or GPe (n=7). SNr- and GPe-DBS, conducted across a wide range of stimulation frequencies, revealed a number of surprising evoked responses, including unexpected CBV decreases within the striatum during DBS at either target, as well as GPe-DBS-evoked positive modulation of frontal cortex. Functional connectivity MRI revealed global modulation of neural networks during DBS at either target, sensitive to stimulation frequency and readily reversed following cessation of stimulation. This work thus contributes to a growing literature demonstrating extensive and unanticipated functional connectivity among basal ganglia nuclei.

Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking.

The basolateral amygdala (BLA) has a crucial role in emotional learning irrespective of valence. The BLA projection to the nucleus accumbens (NAc) is thought to modulate cue-triggered motivated behaviours, but our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural-circuit elements of this pathway selectively during behaviour. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibres from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. Here we show that optical stimulation of the pathway from the BLA to the NAc in mice reinforces behavioural responding to earn additional optical stimulation of these synaptic inputs. Optical stimulation of these glutamatergic fibres required intra-NAc dopamine D1-type receptor signalling, but not D2-type receptor signalling. Brief optical inhibition of fibres from the BLA to the NAc reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behaviour. Moreover, although optical stimulation of glutamatergic fibres from the medial prefrontal cortex to the NAc also elicited reliable excitatory synaptic responses, optical self-stimulation behaviour was not observed by activation of this pathway. These data indicate that whereas the BLA is important for processing both positive and negative affect, the glutamatergic pathway from the BLA to the NAc, in conjunction with dopamine signalling in the NAc, promotes motivated behavioural responding. Thus, optogenetic manipulation of anatomically distinct synaptic inputs to the NAc reveals functionally distinct properties of these inputs in controlling reward-seeking behaviours.

Maternally responsive neurons in the bed nucleus of the stria terminalis and medial preoptic area: Putative circuits for regulating anxiety and reward.

Postpartum neuropsychiatric disorders are a major source of morbidity and mortality and affect at least 10% of childbearing women. Affective dysregulation within this context has been identified in association with changes in reproductive steroids. Steroids promote maternal actions and modulate affect, but can also destabilize mood in some but not all women. Potential brain regions that mediate these effects include the medial preoptic area (mPOA) and ventral bed nucleus of the stria terminalis (vBNST). Herein, we review the regulation of neural activity in the mPOA/vBNST by environmental and hormonal concomitants in puerperal females. Such activity may influence maternal anxiety and motivation and have significant implications for postpartum affective disorders. Future directions for research are also explored, including physiological circuit-level approaches to gain insight into the functional connectivity of hormone-responsive maternal circuits that modulate affect.

Integrating optogenetic and pharmacological approaches to study neural circuit function: current applications and future directions.

Optogenetic strategies to control genetically distinct populations of neurons with light have been rapidly evolving and widely adopted by the neuroscience community as one of the most important tool sets to study neural circuit function. Although optogenetics have already reshaped neuroscience by allowing for more precise control of circuit function compared with traditional techniques, current limitations of these approaches should be considered. Here, we discuss several strategies that combine optogenetic and contemporary pharmacological techniques to further increase the specificity of neural circuit manipulation. We also discuss recent advances that allow for the selective modulation of cellular function and gene expression with light. In addition, we outline a novel application of optogenetic circuit analysis for causally addressing the role of pathway-specific neural activity in mediating alterations in postsynaptic transcriptional processing in genetically defined neurons. By determining how optogenetic activation of specific neural circuits causally contributes to alterations in gene expression in a high-throughput fashion, novel biologic targets for future pharmacological intervention may be uncovered. Lastly, extending this experimental pipeline to selectively target pharmacotherapies to genetically defined neuronal populations or circuits will not only provide more selective control of neural circuits, but also may lead to the development of neural circuit specific pharmacological therapeutics.