Jones Griffith Parker

Striatal spiny-projection neurons (SPNs) integrate glutamatergic inputs from the motor cortex and thalamus with neuromodulatory signals to regulate motor output. In vivo Ca ²⁺ imaging has demonstrated that spatially overlapping ensembles of direct and indirect pathway SPNs (dSPNs, iSPNs) are co-active during spontaneous movement. This co-activity is statistically greater among nearby neurons, correlates with behavioral state, and changes in an SPN-type-specific manner under pathological conditions. How this co-activity arises and whether it is important for movement are not well understood. Co-activity likely arises from shared excitatory inputs, the strength of which are scaled by well-characterized mechanisms of synaptic plasticity. Here, we show that the Group I metabotropic glutamate receptor 5 (mGluR5), which regulates the strength of corticostriatal synapses, is a key mediator of behaviorally relevant SPN co-activity. Pharmacological modulation of mGluR5 signaling bidirectionally altered movement and co-activity, but not the absolute level of activity in dSPNs. Targeted deletion of mGluR5 in dSPNs recapitulated the effects on spatiotemporal neural dynamics and movement, consistent with a striatum-specific effect of mGluR5 modulation. Targeted deletion of mGluR5 also produced changes in the synaptic properties of dSPNs. Separate from any effects on overall activity, our results show that excitatory synaptic modulation influences motor function by coordinating the spatial co-activation of dSPNs in vivo.

The dorsomedial striatum (DMS) is believed to promote action-outcome associations by integrating cortical and limbic afferents with nigrostriatal dopamine. This functional role for the DMS encompasses reinforcement learning processes traditionally ascribed to the ventral (outcome valuation) and lateral (action-selection) subdivisions of the striatum. Previous studies have shown that DMS dopamine signaling encodes actions and outcomes, often in a lateralized manner (e.g., dopamine release is greater for contralateral actions). To determine how these dynamics evolve with changing action-outcome contingencies, we recorded dopamine axon Ca ²⁺ activity in the DMS during a lateralized reversal learning task in mice. Using a miniaturized fluorescence microscope, we found that dopamine axon Ca ²⁺ activation in the DMS encoded actions and outcomes with a lateral bias, but only very early in reversal learning, immediately after the action-outcome contingency switch. Specifically, we found that dopamine axon activation during contralateral choices and the rewards associated with those choices were only greater than ipsilateral choices and their rewards in the first session of reversal. Over the course of reversal, reward- and choice-evoked dopamine axon activation subsided for contralateral, but not ipsilateral, choices, resulting in no lateral bias after learning the new action-outcome contingency. Consistent with a causal role for these lateralized dynamics, unilateral optogenetic inhibition of the nigrostriatal dopamine pathway impaired contralateral reversal by reducing “win-stay” responses. However, this deficit was transient, occurring only during the first reversal session. Our results suggest that dopamine signaling in the DMS facilitates the exploration of new actions, specifically at the specific moment the previous action-outcome contingency becomes conflicted. In our lateralized reversal learning task, this facilitation was particularly important when the new action and resulting outcome were contralateral to the recorded hemisphere. These findings advance our understanding of how the DMS carries out its ascribed role in action-outcome learning.

Background: Fluctuations in striatal dopamine (DA) are interdependent with fluctuations in acetylcho- line (ACh), both of which are thought to be important for motor function and dysfunction in Parkinson’s disease (PD). Objectives: Determine how ACh dynamics are altered by dopamine under normal and parkinsonian conditions following acute and chronic L-DOPA treatment. Methods: We used fiber photometry to record fluorescent DA and ACh sensors in the dorsomedial striatum (DMS) of normal mice treated with vehicle or amphetamine and in the dorsolateral striatum (DLS) of mice with unilateral substantia nigra (SNc) DA neuron lesions (using 6-OHDA) subjected to an L-DOPA-induced dyskinesia (LID) protocol. Results: Under normal conditions, ACh exhibited transient increases followed by pauses and fluctuated at ∼1-Hz frequency in an anti-correlated manner to DA. Amphetamine treatment reduced the frequency of ACh fluctuations and amplitude of ACh transients while prolonging after-transient pauses. In 6-OHDA- lesioned mice, ACh dynamics oscillated at a higher frequency, and ACh events had reduced peaks and pauses. L-DOPA increased DA and, after repeated treatments, also reduced ACh. However, L-DOPA neither restored the anti-correlation between DA and ACh nor normalized the reduced ACh transient and pause amplitudes or the increased frequency of ACh fluctuations. In extended recordings during the tran- sition to the L-DOPA OFF state, ACh remained low as DA diminished, and ACh transient and pause amplitudes remained suppressed, and the oscillatory frequency elevated. Conclusions: Dopamine depletion transforms striatal ACh dynamics and L-DOPA fails to normalize these dynamics. Because these dynamics are unresponsive to treatment, new therapies targeting them may offer symptomatic improvements for PD and LID. Graphical We used dual-wavelength fiber photometry to simultaneously record dopamine and acetylcholine dynam- ics in the dorsal striatum. We recorded these dynamics in control mice before and after treatment with the dopamine releaser amphetamine and in hemiparkinsonian mice before after treatment with the dopamine pre-cursor L-DOPA. We asked how these experimental manipulations alter the bulk signaling of dopa- mine and acetylcholine, their temporal relationship, and the sub-second dynamics of acetylcholine signaling.

Striatal spiny-projection neurons (SPNs) integrate glutamatergic inputs from the motor cortex and thalamus with neuromodulatory signals to regulate motor output. In vivo Ca2+ imaging has demonstrated that spatially overlapping ensembles of direct and indirect pathway SPNs (dSPNs, iSPNs) are co-active during spontaneous movement. This co-activity is statistically greater among nearby neurons, correlates with behavioral state, and changes in an SPN-type-specific manner under pathological conditions. How this co-activity arises and whether is important for movement are not well understood. Co-activity likely arises from shared excitatory inputs, the strength of which are scaled by well-characterized mechanisms of synaptic plasticity. Here, we show that the Group I metabotropic glutamate receptor 5 (mGluR5), which regulates the strength of corticostriatal synapses, is a key mediator of behaviorally relevant SPN co-activity. Pharmacological modulation of mGluR5 signaling bidirectionally altered movement and co-activity, but not the absolute level of activity in dSPNs. Targeted deletion of mGluR5 in dSPNs recapitulated the effects on spatiotemporal neural dynamics and movement, consistent with a striatum-specific effect of mGluR5 modulation. Targeted deletion of mGluR5 also produced changes in the synaptic properties of dSPNs. Separate from any effects on overall activity, our results show that excitatory synaptic modulation influences motor function by coordinating the spatial co-activation of dSPNs in vivo.

Genetically encoded fluorescent sensors of neural activity have become a mainstay of basic neuroscience. However, preclinical drug development has been slower to adopt these tools. Recently, we used miniature microscopes to record Ca²⁺ activity in D1 and D2 dopamine receptor‐expressing spiny projection neurons (SPNs) in response to antipsychotic drugs or candidates. Despite the fact that most antipsychotics block D2 receptors, clinical efficacy was associated with the normalization of D1‐SPN activity under hyperdopaminergic conditions. In this study, we re‐processed these data to approximate a fiber photometry signal and asked whether the conclusions were the same. This re‐evaluation is important because fiber photometry has several advantages over cellular‐resolution imaging. Consistent with our previous finding that bulk and cellular‐resolution imaging report distinct SPN Ca²⁺ dynamics, here the two data types suggested reciprocal effects of drug treatment on D1‐SPN and D2‐SPN Ca²⁺ activity. While amphetamine treatment increased D1‐SPN and decreased D2‐SPN Ca²⁺ event rates in cellular‐resolution data, it increased the fluorescence of individual neurons but decreased their bulk fluorescence in both cell types. Analyzing detected bulk‐fluorescence “events” yielded a closer correlation between the bulk and somatic Ca²⁺ fluorescence. However, it did not fully replicate the results of our previous cellular‐resolution recordings following amphetamine or antipsychotic drug treatment. Our results highlight important distinctions between cellular‐resolution and bulk measurements of in vivo Ca²⁺ activity. While experimenters using in vivo imaging to understand drug effects on neural activity should heed these distinctions, they should also utilize them to gain a more holistic view of drug action.

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder¹. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)²; however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.

Striatal spiny-projection neurons (SPNs) integrate glutamatergic inputs from the motor cortex and thalamus with neuromodulatory signals to regulate motor output. In vivo Ca ²⁺ imaging has demonstrated that spatially overlapping ensembles of direct and indirect pathway SPNs (dSPNs, iSPNs) are co-active during spontaneous movement. This co-activity is statistically greater among nearby neurons, correlates with behavioral state, and changes in an SPN-type-specific manner under pathological conditions. How this co-activity arises and whether is important for movement are not well understood. Co-activity likely arises from shared excitatory inputs, the strength of which are scaled by well-characterized mechanisms of synaptic plasticity. Here, we show that the Group I metabotropic glutamate receptor 5 (mGluR5), which regulates the strength of corticostriatal synapses, is a key mediator of behaviorally relevant SPN co-activity. Pharmacological modulation of mGluR5 signaling bidirectionally altered movement and co-activity, but not the absolute level of activity in dSPNs. Targeted deletion of mGluR5 in dSPNs recapitulated the effects on spatiotemporal neural dynamics and movement, consistent with a striatum-specific effect of mGluR5 modulation. Targeted deletion of mGluR5 also produced changes in the synaptic properties of dSPNs. Separate from any effects on overall activity, our results show that excitatory synaptic modulation influences motor function by coordinating the spatial co-activation of dSPNs in vivo .

Elevated dopamine transmission in psychosis is assumed to unbalance striatal output through D1- and D2-receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2 receptors (D2Rs). In this study, we found that amphetamine-driven dopamine release unbalanced D1-SPN and D2-SPN Ca²⁺ activity in mice, but that antipsychotic efficacy was associated with the reversal of abnormal D1-SPN, rather than D2-SPN, dynamics, even for drugs that are D2R selective or lacking any dopamine receptor affinity. By contrast, a clinically ineffective drug normalized D2-SPN dynamics but exacerbated D1-SPN dynamics under hyperdopaminergic conditions. Consistent with antipsychotic effect, selective D1-SPN inhibition attenuated amphetamine-driven changes in locomotion, sensorimotor gating and hallucination-like perception. Notably, antipsychotic efficacy correlated with the selective inhibition of D1-SPNs only under hyperdopaminergic conditions—a dopamine-state-dependence exhibited by D1R partial agonism but not non-antipsychotic D1R antagonists. Our findings provide new insights into antipsychotic drug mechanism and reveal an important role for D1-SPN modulation.

Summary: Rapid gut-brain communication is critical to maintain energy balance and is disrupted in diet-induced obesity through mechanisms that remain obscure. Specifically, the role of carbohydrate overconsumption in the regulation of interoceptive circuits has been minimally examined in vivo . Here we report that an obesogenic high-sucrose diet (HSD) selectively blunts silencing of hunger-promoting AgRP neurons following intragastric delivery of glucose, whereas we previously showed that overconsumption of a high-fat diet (HFD) selectively attenuates lipid-induced neural silencing. By contrast, both HSD and HFD reversibly dampen rapid AgRP neuron sensory inhibition following chow presentation and promote intake of more palatable foods. Our findings reveal that excess sugar and fat pathologically modulate feeding circuit activity in both macronutrient-dependent and -independent ways, and thus may additively exacerbate obesity.

Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms of schizophrenia. These observations and the fact that increasing brain-wide dopamine improves cognition have fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms. However, this idea has never been explicitly tested with DS-pathway specificity. To determine if excess DS dopamine is involved in cognitive and negative symptoms, we selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social interaction and working memory, behavioral constructs related to negative and cognitive symptoms. We combined this manipulation with antipsychotic treatment (haloperidol) and compared it to brain-wide dopamine release via amphetamine treatment. We found that selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired social interaction and working memory. Haloperidol normalized locomotion, but only partially rescued working memory and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. These results suggest that excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.