Biology subjects

Hamid, A. A.

Publications and source records attributed to Hamid, A. A..

8 recordsLinked to original sources

bioRxiv2026

HSF1 controls transcriptional programs that establish thalamostriatal shaft synaptic architecture and preserve cognitive flexibility

Cognitive flexibility (CF) declines during aging and is further impaired in neurodegenerative diseases such as Huntingtons disease (HD), yet the molecular mechanisms underlying these deficits remain poorly understood. Thalamostriatal (T-S) synapses are critical for CF, and we previously identified Heat Shock Factor 1 (HSF1) as a regulator of T-S density in HD. However, how HSF1 regulates T-S synapses and whether it modulates cognitive flexibility (CF) remained unclear. Here, we combined HSF1 ChIP-seq, transcriptomics, synapto-proteomics, targeted genetic manipulations and behavioral analyses to study how HSF1 regulates T-S synapses and CF. We found HSF1 directly controls a transcriptional program governing postsynaptic architecture and actin cytoskeletal dynamics, which are disrupted in aging and HD. Loss of HSF1 drives selective destabilization of actin patches at T-S shaft synapses and impaired CF decline. Our results underscore a novel function for HSF1 in the regulation of striatal neural circuits with essential implications in the neurobiology of cognitive flexibility.

neuroscience↗

bioRxiv2025

Dual cholinergic mechanisms for sculpting striatal dopamine in vivo

Striatal dopamine (DA) and acetylcholine constitute a computationally powerful neuromodulatory dyad that orchestrates action selection, motivational vigor, and reward learning. Striatal cholinergic interneurons (CINs) synapse onto DA axons and stimulate DA release via {beta}2-containing nicotinic receptors ({beta}2-nAChRs), providing a local modulatory channel distinct from midbrain-derived spikes. Yet whether this mechanism operates in vivo and how it contributes to striatal computations, orthogonal to those facilitated by prediction errors encoded in the DA somata, remains unresolved. Using spatiotemporally precise optogenetic stimulation of CINs paired with ultrafast DA imaging in the dorsal striatum, we identify a biphasic mode of CIN-evoked DA release in awake mice. CIN activation evoked an ultra-fas {beta}2-nAChR-dependent DA transient peaking within ~40 ms that requires millimeter-scale CIN synchrony and is systematically obscured by conventional imaging bandwidths or slow DA sensor kinetics. A second, delayed DA elevation peaking at ~180 ms persisted despite {beta}2-nAChR blockade and is mediated by muscarinic receptors, 7- and 6*-nAChRs, and a non-cholinergic CIN messenger, revealing a previously unrecognized polysynaptic CIN mechanism. Our observations reconcile discrepancies between slice and in vivo studies and show that CINs engage DA release through two mechanistically distinct pathways: (i) an ultra-fast, monosynaptic mode provides a spatially expansive DA signal ideally positioned to reconfigure striatal microcircuits globally, and (ii) a slower, spatially flexible polysynaptic DA mode suited for sustaining ongoing decisions. This dual architecture expands the computational repertoire of striatal DA dynamics in behavioral and cognitive control.

neuroscience↗

bioRxiv2025

Behavioral Opportunism and Altered Dopamine Dynamics in Mice Exposed to Early Life Adversity

Early life adversity (ELA) confers risk for reward-related psychopathologies. These risks may stem from adaptations optimizing reward pursuit in anticipation of unreliable, resource poor environments. One rational adaptation to poor, unreliable environments is Behavioral Opportunism: updating expectations more slowly and acting vigorously only when reward is immediately available. To systematically test the impact of ELA on behavioral strategies and underlying reward processing mechanisms, we exposed mice to resource restriction (limited bedding and nesting materials for 7 days) to manipulate the reliability and quality of early life care. Subsequently, we tested adults reward learning and decision making in a two-arm bandit task and recorded dopamine signaling using dLight1.2 fiber photometry in the nucleus accumbens core. Exposure to ELA led to poorer choice discrimination, impaired learning, and decreased adaptation to changes in reward availability. Furthermore, ELA mice were slower to choose between levers but were faster to retrieve immediately available rewards when delivered, consistent with a strategy of behavioral opportunism. Dopamine signaling predicted behavior in both rearing conditions, and its fluctuations were strongly predictive of faster retrieval in ELA mice and an increased likelihood of choice repetition, implying that aberrant dopamine signals underlie slowed learning and vigorous action for immediately available rewards. To understand key features of maternal interactions driving these effects, we used home cage video monitoring to quantify maternal behaviors, continuously, across early life. We found that specific experiential outcomes, such as maternal kicking, intensified behavioral opportunism in adults, predicting poorer bandit task performance beyond the group effect of ELA. Behavioral opportunism provides an explanatory framework for interpreting altered reward processing and reward pursuit in adulthood for individuals exposed to ELA.

animal behavior and cognition↗

bioRxiv2024

Wideband ratiometric measurement of tonic and phasic dopamine release in the striatum

Reward learning, cognition, and motivation are supported by changes in neurotransmitter levels across multiple timescales. Current measurement technologies for various neuromodulators (such as dopamine and serotonin) do not bridge timescales of fluctuations, limiting the ability to define the behavioral significance, regulation, and relationship between fast (phasic) and slow (tonic) dynamics. To help resolve longstanding debates about the behavioral significance of dopamine across timescales, we developed a novel quantification strategy, augmenting extensively used carbon-fiber Fast Scan Cyclic Voltammetry (FSCV). We iteratively engineered the FSCV scan sequence to rapidly modify electrode sensitivity within a sampling window and applied ratiometric analysis for wideband dopamine measurement. This allowed us to selectively eliminate artifacts unrelated to electrochemical detection (i.e., baseline drift), overcoming previous limitations that precluded wideband dopamine detection from milliseconds to hours. We extensively characterize this approach in vitro, validate performance in vivo with simultaneous microdialysis, and deploy this technique to measure wideband dopamine changes across striatal regions under pharmacological, optogenetic, and behavioral manipulations. We demonstrate that our approach can extend to additional analytes, including serotonin and pH, providing a robust platform to assess the contributions of multi-timescale neuromodulator fluctuations to cognition, learning, and motivation.

neuroscience↗

bioRxiv2022

Loss of tristetraprolin activates NF-κB induced phenotypic plasticity and primes transition to lethal prostate cancer

Phenotypic plasticity is a hallmark of cancer and increasingly realized as a mechanism of resistance in androgen indifferent prostate tumors. It is critical to identify mechanisms and actionable targets driving phenotypic plasticity. Here, we report that loss of tristetraprolin (TTP, gene ZFP36), an RNA binding protein that regulates mRNA stability increases NF-{kappa}B activation and is associated with higher rates of aggressive disease and early recurrence in primary prostate cancer (PCa). We examined the clinical and biological impact of ZFP36 loss combined with PTEN loss, a known driver of PCa. Combined loss of PTEN and ZFP36 expression was associated with increased risk of recurrence in multiple independent primary PCa cohorts, and significantly reduced overall survival and time to progression following castration in genetically engineered mouse models. ZFP36 loss alters the cell state that is driven by PTEN loss, demonstrated by positive enrichment of gene sets including EMT, inflammation, TNF/NF-{kappa}B, IL6-JAK/STAT3. ZFP36 loss also induces enrichment of multiple gene sets involved in cell migration, chemotaxis, and proliferation. Use of the NF-{kappa}B inhibitor dimethylaminoparthenolide induced significant therapeutic responses in tumors with PTEN and ZFP36 co-loss and reversed castration resistance. This work identifies a novel molecular mechanism driving phenotypic plasticity and castration resistance through loss of ZFP36 expression, that can be reversed by inhibition of NF-{kappa}B activity.

cancer biology↗

bioRxiv2021

Abnormal Recovery from Acute Stress in Huntingtons Disease Mice

Introduction: Comparisons of hypothalamic dysfunction between Huntingtons Disease (HD) patients and rodent models of HD have not always yielded similar results. Cortisol levels in HD patients have been contradictory, with reports ranging from hypo- to hypercorticoidism of morning measurements. Initial reports of major elevations in circulating corticosterone levels in the R6/2 mouse model of HD have only been followed up in one other closely related model, the R6/1 mouse, and the results were not perfectly congruent. To determine if abnormal stress hormones were a characteristic of disease, we examined diurnal and stress-induced corticosterone levels in multiple HD mouse models. Methods: We analyzed serum corticosterone levels from R6/2, Q140 and BACHD mice either diurnally (R6/2) or after restraint stress and subsequent recovery (all 3 models). Glucocorticoid secretion was also examined (R6/2) following dexamethasone suppression and ACTH stimulation. Blood samples were collected either by submandibular puncture or as trunk blood at sacrifice. Plasma corticosterone levels were assayed by RIA. Regional brain glucocorticoid receptor (GR) levels were visualized using immunofluorescence. Results: In the R6/2 mouse, basal levels of corticosterone, exhibited normal, sexually dimorphic diurnal rhythms but eventually became elevated towards end of life, after 13 weeks. The ability of the adrenal gland to produce corticosterone was not altered and the adrenal response to ACTH stimulation was only elevated in male R6/2 mice compared to littermates. Down regulation of GR receptors was only observed in the PVN at 16 weeks. R6/2 mice at both 6 and 12 weeks responded equivalently to littermates in the initial corticosterone response to restraint stress but serum corticosterone recovered from stress significantly more slowly. No differences were found in the initial stress response or in the recovery from stress for Q140 or BACHD mice, examined at 12 and 9 months, respectively. Conclusions: We did not find evidence of major disruption in glucocorticoid signaling in HD mouse models. A significantly slowed recovery from stress observed in the R6/2 mouse suggests such disruptions are context dependent. These results suggest that disruption of the HPA axis was subtle and occurred only at advanced stages of disease represented by comparisons among these HD mouse models.

neuroscience↗

bioRxiv2019

Dopamine waves as a mechanism for spatiotemporal credit assignment

Significant evidence supports the view that dopamine shapes reward-learning by encoding prediction errors. However, it is unknown whether dopamine decision-signals are tailored to the functional specialization of target regions. Here, we report a novel set of wave-like spatiotemporal activity-patterns in dopamine axons across the dorsal striatum. These waves switch between different activational motifs and organize dopamine transients into localized clusters within functionally related striatal subregions. These specific motifs are associated with distinct task contexts: At reward delivery, dopamine signals rapidly resynchronize into propagating waves with opponent directions depending on instrumental task contingencies. Moreover, dopamine dynamics during reward pursuit signal the extent to which mice have instrumental control and interact with reward waves to predict future behavioral adjustments. Our results are consistent with a computational architecture in which striatal dopamine signals are sculpted by inference about instrumental controllability and provide evidence for a spatiotemporally \"vectorized\" role of dopamine in credit assignment.

neuroscience↗

bioRxiv2019

Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer

Prostate cancers are considered immunologically cold tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon (IFN) response genes predicts a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models derepresses expression of double-strand RNA (dsRNA), associated with upregulation of genes involved in antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response, including PD-L1. Similarly, application of a novel EZH2 derived gene signature to human prostate sample analysis indicated an inverse correlation between tumor EZH2 activity/expression with T-cell inflamed and IFN gene signatures and PD-L1 expression. EZH2 inhibition combined with PD-1 CPI significantly enhances antitumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI.

cancer biology↗