Biology subjects

Parker, J. G.

Publications and source records attributed to Parker, J. G..

7 recordsLinked to original sources

bioRxiv2025

Parkinsonian striatal acetylcholine dynamics are refractory to L-DOPA treatment

BackgroundFluctuations 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 Parkinsons disease (PD). ObjectivesDetermine how ACh dynamics are altered by dopamine under normal and parkinsonian conditions following acute and chronic L-DOPA treatment. MethodsWe 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. ResultsUnder 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. ConclusionsDopamine 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 Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=72 SRC="FIGDIR/small/686401v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@705b66org.highwire.dtl.DTLVardef@80afd2org.highwire.dtl.DTLVardef@972c41org.highwire.dtl.DTLVardef@da91f8_HPS_FORMAT_FIGEXP M_FIG C_FIG 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.

neuroscience↗

bioRxiv2023

Modulation of the spatiotemporal dynamics of striatal direct pathway neurons and motor output by mGluR5

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.

neuroscience↗

bioRxiv2023

Sucrose overconsumption impairs feeding circuit dynamics and promotes palatable food intake

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.

neuroscience↗

bioRxiv2022

Selective Nigrostriatal Dopamine Excess Impairs Behaviors Linked to the Cognitive and Negative Symptoms of Psychosis

BACKGROUNDExcess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work for positive symptoms by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms. Further, broadly increasing dopamine release improves cognitive function. These observations fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms, but this has never been tested with dopamine pathway specificity. METHODSWe selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of male and female 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 and cognitive function. We combined this manipulation with antipsychotic treatment (haloperidol) and compared the pathway-specific manipulation to treatment with the non-selective dopamine releaser amphetamine. RESULTSSelectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired behavioral processes linked to negative and cognitive symptoms (social drive and working memory). Haloperidol normalized locomotion, 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. CONCLUSIONSExcess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Previous studies using non-selective approaches to release dopamine likely overlooked these contributions of excess dopamine to psychosis. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.

neuroscience↗

bioRxiv2022

Control of flight responses by a non-canonical corticolimbic pathway.

Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as posttraumatic stress and panic disorder.1 Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation to 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. Using a behavioural paradigm that elicits both 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 projections target distinct medial CeA neuronal populations projecting to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.

neuroscience↗

bioRxiv2021

Modulating D1 rather than D2 receptor-expressing spiny-projection neurons corresponds to optimal antipsychotic effect

Overactive dopamine transmission in psychosis is predicted to unbalance striatal output via D1- and D2-dopamine receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2-receptor signaling. Here we imaged D1- and D2-SPN Ca2+ dynamics in mice to determine the neural signatures of antipsychotic effect. Initially we compared effective (clozapine and haloperidol) antipsychotics to a candidate drug that failed in clinical trials (MP-10). Clozapine and haloperidol normalized hyperdopaminergic D1-SPN dynamics, while MP-10 only normalized D2-SPN activity. Clozapine, haloperidol or chemogenetic manipulations of D1-SPNs also normalized sensorimotor gating. Given the surprising correlation between clinical efficacy and D1-SPN modulation, we evaluated compounds that selectively target D1-SPNs. D1R partial agonism, antagonism, or positive M4 cholinergic receptor modulation all normalized the levels of D1-SPN activity, locomotion, and sensorimotor gating. Our results suggest that D1-SPN activity is a more relevant therapeutic target than D2-SPN activity for the development of effective antipsychotics.

neuroscience↗

bioRxiv2018

Calcium imaging in freely-moving mice during electrical stimulation of deep brain structures

After decades of study in humans and animal models, there remains a lack of consensus regarding how the action of electrical stimulation on neuronal and non-neuronal elements - e.g. neuropil, cell bodies, glial cells, etc. - leads to the therapeutic effects of neuromodulation therapies. To further our understanding of neuromodulation therapies, there is a critical need for novel methodological approaches using state-of-the-art neuroscience tools to study neuromodulation therapy in preclinical models of disease. In this manuscript we outline one such approach combining chronic behaving single-photon microendoscope recordings in a pathological mouse model with electrical stimulation of a common deep brain stimulation (DBS) target. We describe in detail the steps necessary to realize this approach, as well as discuss key considerations for extending this experimental paradigm to other DBS targets for different therapeutic indications. Additionally, we make recommendations from our experience on implementing and validating the required combination of procedures that includes: the induction of a pathological model (6-OHDA model of Parkinsons disease) through an injection procedure, the injection of the viral vector to induce GCaMP expression, the implantation of the GRIN lens and stimulation electrode, and the installation of a baseplate for mounting the microendoscope. We proactively identify unique data analysis confounds occurring due to the combination of electrical stimulation and optical recordings and outline an approach to address these confounds. In order to validate the technical feasibility of this unique combination of experimental methods, we present data to demonstrate that 1) despite the complex multifaceted surgical procedures, chronic optical recordings of hundreds of cells combined with stimulation is achievable over week long periods 2) this approach enables measurement of differences in DBS evoked neural activity between anesthetized and awake conditions and 3) this combination of techniques can be used to measure electrical stimulation induced changes in neural activity during behavior in a pathological mouse model. These findings are presented to underscore the feasibility and potential utility of minimally constrained optical recordings to elucidate the mechanisms of DBS therapies in animal models of disease.

bioengineering↗