Biology subjects

Weber, M. A.

Publications and source records attributed to Weber, M. A..

15 recordsLinked to original sources

bioRxiv2026

Dorsomedial striatal dopamine ramps down during interval timing

Dopamine is involved in disorders that degrade cognition such as Parkinsons disease, ADHD, addiction, and schizophrenia; however, it is unclear how dopamine modulates brain circuits involved in cognitive processing. We investigated this problem by recording dopamine during interval timing, an elementary task that requires executive functions to estimate an interval of several seconds by making a motor response. We harnessed the fluorescent dopamine sensor dLight1.3b to record relative dopamine dynamics in the mouse dorsomedial striatum, which integrates information from cognitive cortical circuits and is required for interval timing. We found that: 1) dopamine activity ramped down during interval timing prior to increasing at reward delivery; 2) dopamine ramping dynamics predicted interval timing behavior; and 3) dopamine ramping dynamics were distinct between male and female mice and affected by amphetamine, a potent modulator of dopamine. These data provide insight into how dopamine modulates striatal circuits during interval timing and help better understand how dopamine dynamics contribute to cognitive dysfunction in dopamine-related brain diseases.

neuroscience↗

bioRxiv2026

Gut bacterial Infection drives Parkinsonian pathology in LRRK2 G2019S Knock-in Mice

The LRRK2 G2019S mutation is one of the most common genetic risk factors for Parkinsons disease (PD), yet LRRK2 G2019S knock-in (KI) mice rarely develop robust neurodegeneration under basal conditions, suggesting that additional environmental triggers are required for disease progression. Here, we established a clinically relevant gene-environment interaction mouse model of PD by subjecting LRRK2 G2019S KI mice to recurrent Citrobacter (C.) rodentium infection, a murine model of enteric bacterial inflammation. Repeated infection induced progressive PD-like phenotypes selectively in KI mice, including motor impairment, reduced locomotor activity, impaired motor coordination, selective nigrostriatal dopaminergic neurodegeneration, enhanced neuroinflammation, and pathological phosphorylated -synuclein (p-Syn) accumulation, whereas wild-type (WT) mice remained largely resistant. Mechanistically, infected KI mice developed markedly exacerbated colonic inflammation, epithelial barrier dysfunction, increased intestinal permeability, and enhanced inflammasome activation despite normal bacterial clearance, indicating that pathogenic LRRK2 signaling amplifies inflammatory responses rather than impairing antimicrobial defense. In parallel, recurrent infection induced pronounced intestinal p-Syn accumulation and expansion of pathology beyond the epithelial layer in KI mice, supporting a gut-brain axis mechanism linking intestinal inflammation to neurodegeneration. Collectively, these findings demonstrate that the LRRK2 G2019S mutation functions as a sensitizing factor that cooperates with recurrent enteric inflammation to drive PD- related pathology. This study establishes a physiologically relevant LRRK2 G2019S gene- environment interaction mouse model that recapitulates key behavioral, neuropathological, and inflammatory features of PD.

immunology↗

bioRxiv2026

Neuronal ramping and theta power during freely-moving and head-fixed mouse interval timing.

An important paradigm to study executive function is interval timing, which requires participants to estimate a temporal interval, often with a motor response. Interval timing translates from rodents to humans and can model neurodegenerative and neuropsychiatric disease. Interval timing also has parallel, time-dependent neurophysiology in rodents and humans, including time-dependent linear changes in neuronal firing rates over a temporal interval (ramping activity) and low-frequency [~]4 Hz "theta" activity evoked by trial start and response. Despite these translational features, an important confound of interval timing is movement and motor preparation, as participants must report their estimates by planning a movement. To address this confound, we first trained a group of 7 mice in a freely-moving interval timing task in which mice had to move across an operant chamber and nosepoke at the correct time to receive food reward. These mice were then trained in a head-fixed version of interval timing in which mice receive liquid reward for holding still for 3 seconds at the correct location, with reward access randomized to probe interval timing behavior. Despite vastly different motor sequences, we found prominent ramping activity in mouse prefrontal cortex ensembles and prefrontal cortical [~]4 Hz activity evoked both by trial start and preceding the timed decision. These data provide evidence that prefrontal neuronal ramping and theta activity is not linked to a specific motor program but rather a feature of the temporal organization of behavior.

animal behavior and cognition↗

bioRxiv2025

Ventral tegmental area dopamine controls timing variability

Precision defines successful behavior, yet the brain mechanisms promoting precision are unclear. Here, we dissect dopaminergic circuits controlling precision along a single behavioral dimension - the timing of action. We use an interval timing paradigm that requires participants to indicate their estimate of an interval of several seconds with a motor response. We find that humans with Parkinsons disease (PD) had increased timing variability that predicted PD-related cognitive deficits and executive dysfunction. Surprisingly, lesioning ventral tegmental area (VTA) dopamine neurons increased temporal variability. Further, GCaMP6s fiber photometry demonstrated that VTA dopamine neuron activity is strongly modulated at the start of temporal intervals, and that this trial start-related activity predicted temporal variability. Finally, we found that stimulation of VTA dopamine neurons improved timing by decreasing temporal variability in both intact and dopamine-depleted animals. Our data establish a model of cognitive symptoms of human PD and provide insight into the neuronal control of temporal variability, which impacts a wide range of executive functions.

neuroscience↗

bioRxiv2025

Timing, movement, and reward contributions to prefrontal and striatal ramping activity

Across species, prefrontal and striatal neurons exhibit time-dependent ramping activity, defined as a consistent monotonic change in firing rate across temporal intervals. However, it is unclear if ramping activity is related to the cognitive process of estimating time, or to other behavioral factors such as anticipating reward or regulating movements. Here, we harnessed two novel approaches to determine how these factors contribute to prefrontal and striatal ramping activity in mice performing an interval timing task. First, to determine how movement contributes to ramping activity, we tracked movement velocity using DeepLabCut as well as task-specific movements while recording prefrontal or striatal ensembles during interval timing. We found that time was more accurately decoded by ramping neurons than movement-modulated neurons, with the exception of prefrontal velocity-modulated neurons. Second, to disambiguate temporal signals from anticipatory reward signals we compared activity patterns in neurons that were recorded during interval timing to the same neurons recorded during a Pavlovian conditioning task. We found more ramping activity and more accurate temporal decoding by neuronal ensembles during interval timing compared to Pavlovian conditioning. Together, these data quantify contributions of time estimation, movement, and reward anticipation in prefrontal and striatal ensembles, and they suggest that ramping is a cognitive signal that estimates time. Our results provide insight into how prefrontal and striatal ensembles multiplex information to effect temporal control of action.

neuroscience↗

bioRxiv2025

Diverse activity in prefrontal projections promotes temporal control of action

Prefrontal neurons can have diverse activity during cognitive functions like working memory, attention, and timing; however, the importance of this heterogeneity is unclear. Our goal was to better understand the diversity of prefrontal activity through connectivity. We harnessed circuit-specific tools to capture activity within prefrontal projections during interval timing, an elementary cognitive process that requires working memory for temporal rules and attention to the passage of time to estimate a temporal interval of several seconds. We used human electroencephalography and single neuronal recordings in mice to capture prefrontal activity during interval timing, with major patterns characterized by time-dependent ramping (monotonic changes) over a temporal interval. We then leveraged retrograde viruses to interrogate prefrontal cortex (PFC) projections to the mediodorsal thalamus (PFC-MD) and to the dorsomedial striatum (PFC-DMS). We report three novel results. First, circuit-specific calcium fiber photometry revealed that PFC-MD and PFC-DMS activity encoded distinct temporal signals, with PFC-MD projections ramping down and PFC-DMS ramping up to interval timing response times. Second, circuit-specific inactivation revealed that PFC-DMS inactivation disrupted animals internal estimates of time. Third, circuit-specific single-nucleus RNA sequencing of prefrontal projections revealed distinct transcriptomic profiles between PFC-MD and PFC-DMS projections, with enriched genes for cortical layers and neuromodulators, and specific genes such as Cux2, Camk2n1, Htr4, and Foxp2. These data suggest differences in gene expression and connectivity give rise to the diversity of prefrontal activity during interval timing. These findings advance our fundamental understanding of prefrontal function and dysfunction in human disease.

neuroscience↗

bioRxiv2025

Glycolysis-enhancing alpha 1-adrenergic antagonists are neuroprotective in Alzheimers disease

Terazosin (TZ) is an 1-adrenergic receptor antagonist that enhances glycolysis by activating the enzyme phosphoglycerate kinase 1 (PGK1). Epidemiological data suggest that TZ may be neuroprotective in Parkinsons disease and in dementia with Lewy bodies and that glycolysis-enhancing drugs might be protective in other neurodegenerative diseases involving protein aggregation, such as Alzheimers disease (AD). We investigated TZ in AD and report four main results. First, we found that TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired energy homeostasis and reduced the aggregation of the AD-associated protein, amyloid beta (A{beta}) 42. Second, in an AD transgenic mouse model (5xFAD) we found that TZ attenuated amyloid pathology in the hippocampus and rescued cognitive impairments in spatial memory and interval timing behavioral assays. Third, using the Alzheimers Disease Neuroimaging Initiative (ADNI) database, we found that AD patients newly started on TZ or related glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and neuroimaging biomarkers, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), a measure of brain metabolism. Finally, in a large human administrative dataset, we found that patients taking TZ or related glycolysis-enhancing drugs had a lower hazard of being diagnosed with AD compared to those taking tamsulosin or 5-alpha reductase inhibitors. These data further implicate metabolism in neurodegenerative diseases and suggest that glycolysis-enhancing drugs may be neuroprotective in AD.

neuroscience↗

bioRxiv2024

Long-term, cell type-specific effects of prenatal stress on dorsal striatum and relevant behaviors in mice

Maternal stress during pregnancy, or prenatal stress, is a risk factor for neurodevelopmental disorders in offspring, including autism spectrum disorder (ASD). In ASD, dorsal striatum displays abnormalities correlating with symptom severity, but there is a gap in knowledge about dorsal striatal cellular and molecular mechanisms that may contribute. Using a mouse model, we investigated how prenatal stress impacted striatal-dependent behavior in adult offspring. We observed enhanced motor learning and earlier response times on an interval timing task, with accompanying changes in time-related medium spiny neuron (MSN) activity. We performed adult dorsal striatal single-cell RNA sequencing following prenatal stress which revealed differentially expressed genes (DEGs) in multiple cell types; downregulated DEGs were enriched for ribosome and translational pathways consistently in MSN subtypes, microglia, and somatostatin neurons. DEGs in MSN subtypes over-represented ASD risk genes and were enriched for synapse-related processes. These results provide insights into striatal alterations relevant to neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Amphetamine increases timing variability by degrading prefrontal ramping activity

BackgroundAmphetamine is a commonly abused psychostimulant that increases synaptic catecholamine levels and impairs executive functions. However, it is unknown how acute amphetamine affects brain areas involved in executive control, such as the prefrontal cortex. We studied this problem in mice using interval timing, which requires participants to estimate an interval of several seconds with a motor response. Rodent prefrontal cortex ensembles are required for interval timing. We tested the hypothesis that amphetamine disrupts interval timing by degrading prefrontal cortex temporal encoding. MethodsWe first quantified the effects of amphetamine on interval timing performance by conducting a meta-analysis of 11 prior rodent studies. We also implanted multielectrode recording arrays in the dorsomedial prefrontal cortex of 7 mice and then examined the effects of 1.5 mg/kg D-amphetamine injected intraperitoneally on interval timing behavior and prefrontal neuronal ensemble activity. ResultsA meta-analysis of previous literature revealed that amphetamine produces a large effect size on interval timing variability across studies but only a medium effect size on central tendencies of interval timing. We found a similar effect on interval timing variability in our task, which was accompanied by greater trial-to-trial variability in prefrontal ramping, attenuated interactions between pairs of ramping neurons, and dampened low-frequency oscillations. ConclusionsThese findings suggest that amphetamine alters prefrontal temporal processing by increasing the variability of prefrontal ramping. Our work provides insight into how amphetamine affects timing-related brain activity, which may be useful in developing new neurophysiological markers for amphetamine use and novel treatments targeting the prefrontal cortex.

neuroscience↗

bioRxiv2023

Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse

Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). EtOH is the most abused substance worldwide with chronic consumption often leading to the development of dependence and abuse. Unfortunately, the neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6fl/fl; DAT-iCreER mice to determine the role of RGS6 in VTA DA neurons on EtOH consumption and reward behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse VTA, and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in VTA DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6-/- mice. Strikingly, RGS6 loss from VTA DA neurons before or after EtOH behavioral reward is established significantly reduced ([~]50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies illuminate a critical role of RGS6 in the mesolimbic circuit in promoting EtOH seeking, reward, and reinstatement. We propose that RGS6 functions to promote DA transmission through its function as a negative modulator of GPCR-Gi/o-DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.

neuroscience↗

bioRxiv2023

Complementary cognitive roles for D2-MSNs and D1-MSNs in interval timing

The role of striatal pathways in cognitive processing is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds and involves working memory for temporal rules as well as attention to the passage of time. We harnessed optogenetic tagging to record from striatal D2- dopamine receptor-expressing medium spiny neurons (D2-MSNs) in the indirect pathway and from D1-dopamine receptor-expressing MSNs (D1-MSNs) in the direct pathway. We found that D2-MSNs and D1-MSNs exhibited distinct dynamics over temporal intervals as quantified by principal component analyses and trial-by-trial generalized linear models. MSN recordings helped construct and constrain a four-parameter drift-diffusion computational model in which MSN ensemble activity represented the accumulation of temporal evidence. This model predicted that disrupting either D2-MSNs or D1-MSNs would increase interval timing response times and alter MSN firing. In line with this prediction, we found that optogenetic inhibition or pharmacological disruption of either D2-MSNs or D1-MSNs increased interval timing response times. Pharmacologically disrupting D2-MSNs or D1-MSNs also changed MSN dynamics and degraded trial-by-trial temporal decoding. Together, our findings demonstrate that D2-MSNs and D1-MSNs had opposing dynamics yet played complementary cognitive roles, implying that striatal direct and indirect pathways work together to shape temporal control of action. These data provide novel insight into basal ganglia cognitive operations beyond movement and have implications for human striatal diseases and therapies targeting striatal pathways.

neuroscience↗

bioRxiv2023

Sex similarities and dopaminergic differences in interval timing

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing represenation in behavioral neuroscience.

neuroscience↗

bioRxiv2023

Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily impact cortical and subcortical structures and lead to restricted behavioral impacts

Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops -syn aggregates in DLB and PDD. To investigate the consequences of -syn pathology in the cortex, we injected human -syn pre-formed fibrils into the PFC of wildtype mice. We report that PFC PFFs: 1) induced -syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; 3) increased open field exploration; and 4) did not affect susceptibility to an inflammatory challenge. This model of cortical-dominant pathology aids in our understanding of how local -syn aggregation might impact some symptoms in PDD and DLB.

animal behavior and cognition↗

bioRxiv2022

Mice expressing P301S mutant human tau have deficits in interval timing

Interval timing is a key executive process that involves estimating the duration of an interval over several seconds or minutes. Patients with Alzheimers disease (AD) have deficits in interval timing. Since temporal control of action is highly conserved across mammalian species, studying interval timing tasks in animal AD models may be relevant to human disease. Amyloid plaques and tau neurofibrillary tangles are hallmark features of AD. While rodent models of amyloid pathology are known to have interval timing impairments, to our knowledge, interval timing has not been studied in models of tauopathy. Here, we evaluate interval timing performance of P301S transgenic mice, a widely studied model of tauopathy that overexpresses human tau with the P301S mutation. We employed the switch interval timing task, and found that P301S mice consistently underestimated temporal intervals compared to wild-type controls, responding early in anticipation of the target interval. Our study indicating timing deficits in a mouse tauopathy model could have relevance to human tauopathies such as AD. HIGHLIGHTSO_LIWe examined interval timing behavior in mice expressing P301S mutant tau C_LIO_LIP301S mice responded earler than littermate controls C_LIO_LIThese data provide insight into animal models of tauopathy C_LI

neuroscience↗

bioRxiv2021

Quantifying the inverted U: A meta-analysis of prefrontal dopamine, D1-receptors, and working memory

Dopamine in the prefrontal cortex can be disrupted in human disorders that affect cognitive function such as Parkinsons disease (PD), attention-deficit hyperactivity disorder (ADHD), and schizophrenia. Dopamine has a powerful effect on prefrontal circuits via the D1-type dopamine receptor (D1DR). It has been proposed that prefrontal dopamine has "inverted U-shaped" dynamics, with optimal dopamine and D1DR signaling required for optimal cognitive function. However, the quantitative relationship between prefrontal dopamine and cognitive function is not clear. Here, we conducted a meta-analysis of published manipulations of prefrontal dopamine and the effects on working memory, a high-level executive function in humans, primates, and rodents that involves maintaining and manipulating information over seconds to minutes. We reviewed 646 papers and found that 75 studies met criteria for inclusion. Our quantification of effect sizes for dopamine, D1DRs, and behavior revealed a negative quadratic slope. This is consistent with the proposed inverted U-shape of prefrontal dopamine and D1DRs and working memory performance, explaining 10% of the variance. Of note, the inverted quadratic fit was much stronger for prefrontal D1DRs alone, explaining 26% of the variance, compared to prefrontal dopamine alone, explaining 10% of the variance. Taken together, these data, derived from a variety of manipulations and systems, demonstrate that optimal prefrontal dopamine signalling is linked with higher cognitive function. Our results provide insight into the fundamental dynamics of prefrontal dopamine, which could be useful for pharmacological interventions targeting prefrontal dopaminergic circuits, and into the pathophysiology of human brain disease.

neuroscience↗