Biology subjects

Atwood, B.

Publications and source records attributed to Atwood, B..

5 recordsLinked to original sources

bioRxiv2024

Deletion of endocannabinoid synthesizing enzyme DAGLα from cerebellar Purkinje cells decreases social preference and elevates anxiety

The endocannabinoid (eCB) signaling system is robustly expressed in the cerebellum starting from the embryonic developmental stages to adulthood. There it plays a key role in regulating cerebellar synaptic plasticity and excitability, suggesting that impaired eCB signaling will lead to deficits in cerebellar adjustments of ongoing behaviors and cerebellar learning. Indeed, human mutations in DAGL are associated with neurodevelopmental disorders. In this study, we show that selective deletion of the eCB synthesizing enzyme diacylglycerol lipase alpha (Dagl) from mouse cerebellar Purkinje cells (PCs) alters motor and social behaviors, disrupts short-term synaptic plasticity in both excitatory and inhibitory synapses, and reduces Purkinje cell activity during social exploration. Our results provide the first evidence for cerebellar-specific eCB regulation of social behaviors and implicate eCB regulation of synaptic plasticity and PC activity as the neural substrates contributing to these deficits. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/607068v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@1a0a1d8org.highwire.dtl.DTLVardef@e17f34org.highwire.dtl.DTLVardef@665a75org.highwire.dtl.DTLVardef@1bcc7f1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Cerebellar anatomy, morphology of Purkinje cells, localization, density, and spontaneous activity of excitatory and inhibitory synapses are normal in cerebellar-Purkinje-cell-specific Dagl KOs. However, endocannabinoid-dependent short-term synaptic plasticity (DSE and DSI) and activity of Purkinje cells in lobe VI during social exploration are dramatically reduced, and the KO mice exhibit alterations in sensorimotor coordination, deceased social preference, and increased anxiety. C_FIG

neuroscience↗

bioRxiv2023

SEX-DEPENDENT ENGAGEMENT OF ANTERIOR INSULAR CORTEX INPUTS TO THE DORSOLATERAL STRIATUM IN BINGE ALCOHOL DRINKING

How does alcohol consumption alter synaptic transmission across time, and do these alcohol-induced neuroadaptations occur similarly in both male and female mice? Previous work shows that anterior insular cortex (AIC) projections to the dorsolateral striatum (DLS) are uniquely sensitive to alcohol-induced neuroadaptations in male, but not female mice, and play a role in governing binge alcohol consumption in male mice. Here, by using high-resolution behavior data paired with in-vivo fiber photometry, we show how similar levels of alcohol intake are achieved via different behavioral strategies across sex, and how inter-drinking session thirst states predict future alcohol intakes in females, but not males. Further, we show how presynaptic calcium activity recorded from AIC synaptic inputs in the DLS across 3 weeks of water consumption followed by 3 weeks of binge alcohol consumption change across, fluid, time, sex, and brain circuit lateralization. By time-locking presynaptic calcium activity from AIC inputs to the DLS to peri-initiation of drinking events we also show that AIC inputs into the left DLS robustly encode binge alcohol intake behaviors relative to water consumption and AIC inputs into the right DLS in males, but not females. These findings suggest a fluid-, sex- and lateralization-dependent role for the engagement of AIC inputs into the DLS that encode binge alcohol consumption behaviors and further contextualize alcohol-induced neuroadaptations at AIC inputs to the DLS.

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bioRxiv2022

Prenatal methadone exposure selectively alters protein expression in primary motor cortex: implications for synaptic function

As problematic opioid use has reached epidemic levels over the past two decades, the annual prevalence of opioid use disorder (OUD) in pregnant women has also increased 333%. Yet, how opioids affect the developing brain of offspring from mothers experiencing OUD remains understudied and not fully understood. Animal models of prenatal opioid exposure have discovered many deficits in the offspring of prenatal opioid exposed mothers, such as delays in the development of sensorimotor function and long-term locomotive hyperactivity. In attempt to further understand these deficits and link them with protein changes driven by prenatal opioid exposure, we used a mouse model of prenatal methadone exposure (PME) and preformed an unbiased multi-omic analysis across many sensoriomotor brain regions known to interact with opioid exposure. The effects of PME exposure on the primary motor cortex (M1), primary somatosensory cortex (S1), the dorsomedial striatum (DMS), and dorsolateral striatum (DLS) were assessed using quantitative proteomics and phosphoproteomics. PME drove many changes in protein and phosphopeptide abundance across all brain regions sampled. Gene and gene ontology enrichments were used to assess how protein and phosphopeptide changes in each brain region were altered. Our findings showed that M1 was uniquely affected by PME in comparison to other brain regions. PME uniquely drove changes in M1 glutamatergic synapses and synaptic function. Immunohistochemical analysis also identified anatomical differences in M1 for upregulating the density of glutamatergic and downregulating the density of GABAergic synapses due to PME. Lastly, comparisons between M1 and non-M1 multi-omics revealed conserved brain wide changes in phosphopeptides associated with synaptic activity and assembly, but only specific protein changes in synapse activity and assembly were represented in M1. Together, our studies show that lasting changes in synaptic function driven by PME are largely represented by protein and anatomical changes in M1, which may serve as a starting point for future experimental and translational interventions that aim to reverse the adverse effects of PME on offspring.

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bioRxiv2022

Anterior insular cortex inputs to the dorsolateral striatum govern the maintenance of binge alcohol drinking

How does binge drinking alcohol change synaptic function, and do these changes maintain binge consumption? The anterior insular cortex (AIC) and dorsolateral striatum (DLS) are brain regions implicated in alcohol use disorder. In mice, we found that binge drinking alcohol produced glutamatergic synaptic adaptations selective to AIC inputs within the DLS. Photoexciting AIC[->]DLS circuitry during binge drinking decreased alcohol, but not water consumption and altered alcohol drinking mechanics. Further, drinking mechanics alone from drinking session data predicted alcohol-related circuit changes. AIC[->]DLS manipulation did not alter operant, valence, or anxiety-related behaviors. These findings suggest that alcohol-mediated changes at AIC inputs govern behavioral sequences that maintain binge drinking and may serve as a circuit-based biomarker for the development of alcohol use disorder.

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bioRxiv2019

Basal Ganglia role in learning rewarded actions and executing previously learned choices: healthy and diseased states

The basal ganglia (BG) is a collection of nuclei located deep beneath the cerebral cortex that is involved in learning and selection of rewarded actions. Here, we analyzed BG mechanisms that enable these functions. We implemented a rate model of a BG-thalamo-cortical loop and simulated its performance in a standard action selection task. We have shown that potentiation of corticostriatal synapses enables learning of a rewarded option. However, these synapses became redundant later as direct connections between prefrontal and premotor cortices (PFC-PMC) were potentiated by Hebbian learning. After we switched the reward to the previously unrewarded option (reversal), the BG was again responsible for switching to the new option. Due to the potentiated direct cortical connections, the system was biased to the previously rewarded choice, and establishing the new choice required a greater number of trials. Guided by physiological research, we then modified our model to reproduce pathological states of mild Parkinsons and Huntingtons diseases. We found that in the Parkinsonian state PMC activity levels become extremely variable, which is caused by oscillations arising in the BG-thalamo-cortical loop. The model reproduced severe impairment of learning and predicted that this is caused by these oscillations as well as a reduced reward prediction signal. In the Huntington state, the potentiation of the PFC-PMC connections produced better learning, but altered BG output disrupted expression of the rewarded choices. This resulted in random switching between rewarded and unrewarded choices resembling an exploratory phase that never ended. Our results reconcile the apparent contradiction between the critical involvement of the BG in execution of previously learned actions and yet no impairment of these actions after BG output is ablated by lesions or deep brain stimulation. We predict that the cortico-BG-thalamo-cortical loop conforms to previously learned choice in healthy conditions, but impedes those choices in disease states.\n\nAuthor summaryLearning and selection of a rewarded action, as well as avoiding punishments, are known to involve interaction of cortical and subcortical structures in the brain. The subcortical structure that is included in this interaction is called Basal Ganglia (BG). Accordingly, diseases that damage BG, such as Parkinson and Huntington, disrupt action selection functions. A long-standing puzzle is that abolition of the BG output that disconnects the BG-cortical interaction does not disrupt execution of previously learned actions. This is the principle that is suggested to underlie standard Parkinsonian treatments, such as deep brain stimulation. We model the BG-cortical interaction and reconcile this apparent contradiction. Our simulations show that, while BG is necessary for learning of new rewarded choices, it is not necessary for the expression of previously learned actions. Our model predicts that the BG conforms to previously learned choice in healthy conditions, but impedes those choices in disease states.

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