Biology subjects

Foster, D. J.

Publications and source records attributed to Foster, D. J..

7 recordsLinked to original sources

bioRxiv2026

Striatal M4 Receptors Mediate M4 PAM Antipsychotic-like Efficacy Independently of Normalizing Striatal Dopamine Release

Muscarinic acetylcholine receptor (mAChR) drugs have emerged as a promising new class of antipsychotics, highlighted by the FDA approval of Cobenfy, the first treatment for schizophrenia that does not directly target dopamine receptors. The M4 receptor subtype is thought to be a key mediator of antipsychotic-like efficacy. However, the in vivo circuit mechanisms underlying the antipsychotic-like efficacy observed with M4-selective positive allosteric modulators (PAMs) remain incompletely understood. Here, we used fiber photometry in awake, behaving mice to assess how the M4 PAM VU0467154 (VU'154) affects striatal dopamine (DA) transmission under basal and amphetamine-stimulated conditions. We also generated and validated dorsal striatum-specific M4 knockout mice (DS-M4-KO) to test the role of striatal M4 receptors in regulating DA release and antipsychotic-like effects. VU'154 dose-dependently reduced the amplitude of striatal DA release events under basal conditions without altering event frequency. However, VU'154 had no significant effects on tonic DA levels under basal conditions, as assessed using the D1 PAM DETQ. Despite robustly attenuating AHL, VU'154 produced little to no effect on amphetamine-induced DA levels, indicating that antipsychotic-like efficacy was dissociated from changes in striatal DA levels. Notably, VU'154 efficacy in AHL was absent in DS-M4-KO mice, demonstrating that M4 receptors in the dorsal striatum are required for antipsychotic-like effects. Combined with previous studies implicating a key role for M4 receptors on D1-expressing neurons, these findings suggest that M4 PAMs produce antipsychotic-like efficacy primarily through postsynaptic mechanisms in the dorsal striatum, rather than through broad normalization of amphetamine-induced DA release.

pharmacology and toxicology↗

bioRxiv2026

Spatial goals trap hippocampal replay

Hippocampal replay is proposed to support memory and planning by preferentially reactivating behaviorally significant locations. Although learning can alter which locations are reactivated and how frequently, whether it also alters the dynamics by which replay propagates through the cognitive map remains unknown. To address this, we recorded large-scale CA1 activity while rats collected identical rewards at multiple spatial locations, only one of which was consistently rewarded and served as the Goal. Replay events occurred nearly twice as often during reward consumption at the Goal compared to Non-Goal sites and were accompanied by reduced inhibition. Goal-associated replays were also slower, shorter, and more locally confined. Replays originating elsewhere in the arena slowed and preferentially terminated when nearing the Goal, indicating that the Goal locally resists replay propagation regardless of where the replay was initiated. Increasing evidence suggests that hippocampal sequences arise from adaptation-like mechanisms that propagate neural activity away from recently active states. We hypothesized that the slowing and spatial confinement of Goal-associated replay arises from reduced effective adaptation near the Goal. A recurrent network model showed that reducing adaptation strength reproduces these effects and correctly predicted increased population firing rates and weaker avoidance of recently traveled or reactivated paths. Finally, we found evidence for reduced interneuron-mediated feedback inhibition near the Goal, providing a potential circuit mechanism for locally modulating adaptation. Our findings show that learning locally reshapes the dynamics governing internally generated activity, causing replay to linger near behaviorally significant locations and providing a new mechanism for their preferential reactivation.

neuroscience↗

bioRxiv2024

Self-avoidance dominates the selection of hippocampal replay

Spontaneous neural activity sequences are generated by the brain in the absence of external input1-12, yet how they are produced remains unknown. During immobility, hippocampal replay sequences depict spatial paths related to the animals past experience or predicted future13. By recording from large ensembles of hippocampal place cells14 in combination with optogenetic manipulation of cortical input in freely behaving rats, we show here that the selection of hippocampal replay is governed by a novel self-avoidance principle. Following movement cessation, replay of the animals past path is strongly avoided, while replay of the future path predominates. Moreover, when the past and future paths overlap, early replays avoid both and depict entirely different trajectories. Further, replays avoid self-repetition, on a shorter timescale compared to the avoidance of previous behavioral trajectories. Eventually, several seconds into the stopping period, replay of the past trajectory dominates. This temporal organization contrasts with established and recent predictions9,10,15,16 but is well-recapitulated by a symmetry-breaking attractor model of sequence generation in which individual neurons adapt their firing rates over time26-35. However, while the model is sufficient to produce avoidance of recently traversed or reactivated paths, it requires an additional excitatory input into recently activated cells to produce the later window of past-dominance. We performed optogenetic perturbations to demonstrate that this input is provided by medial entorhinal cortex, revealing its role in maintaining a memory of past experience that biases hippocampal replay. Together, these data provide specific evidence for how hippocampal replays are generated.

neuroscience↗

bioRxiv2022

Robust and durable prophylactic protection conferred by RNA interference in preclinical models of SARS-CoV-2

RNA interference is a natural antiviral mechanism that could be harnessed to combat SARS-CoV-2 infection by targeting and destroying the viral genome. We screened lipophilic small-interfering RNA (siRNA) conjugates targeting highly conserved regions of the SARS-CoV-2 genome and identified leads targeting outside of the spike-encoding region capable of achieving [≥]3-log viral reduction. Serial passaging studies demonstrated that a two-siRNA combination prevented development of resistance compared to a single-siRNA approach. A two-siRNA combination delivered intranasally protected Syrian hamsters from weight loss and lung pathology by viral infection upon prophylactic administration but not following onset of infection. Together, the data support potential utility of RNAi as a prophylactic approach to limit SARS-CoV-2 infection that may help combat emergent variants, complement existing interventions, or protect populations where vaccines are less effective. Most importantly, this strategy has implications for developing medicines that may be valuable in protecting against future coronavirus pandemics.

pharmacology and toxicology↗

bioRxiv2021

Genome-wide CRISPR interference screen identifies long non-coding RNA loci required for differentiation and pluripotency

Although many long non-coding RNAs (lncRNAs) exhibit lineage-specific expression, the vast majority remain functionally uncharacterized in the context of development. Here, we report the first described human embryonic stem cell (hESC) lines to repress (CRISPRi) or activate (CRISPRa) transcription during differentiation into all three germ layers, facilitating the modulation of lncRNA expression during early development. We performed an unbiased, genome-wide CRISPRi screen targeting thousands of lncRNA loci expressed during endoderm differentiation. While dozens of lncRNA loci were required for proper differentiation, most differentially expressed lncRNAs were not, supporting the necessity for functional screening instead of relying solely on gene expression analyses. In parallel, we developed a clustering approach to infer mechanisms of action of lncRNA hits based on a variety of genomic features. We subsequently identified and validated FOXD3-AS1 as a functional lncRNA essential for pluripotency and differentiation. Taken together, the cell lines and methodology described herein can be adapted to discover and characterize novel regulators of differentiation into any lineage.

molecular biology↗

bioRxiv2020

Discovery of the first selective M4 muscarinic acetylcholine receptor antagonists with in vivo anti-parkinsonian and anti-dystonic efficacy

Non-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti-muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti-parkinsonian and anti-dystonic efficacy observed with the use of non-selective anti-muscarinic therapeutics. Our recent work has indicated that the M4 muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4 may recapitulate the efficacy of non-selective anti-muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here we utilize genetic mAChR knockout animals in combination with non-selective mAChR antagonists to confirm that the M4 receptor underlies the locomotor-stimulating and anti-parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4 antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.

pharmacology and toxicology↗

bioRxiv2018

Uncovering temporal structure in hippocampal output patterns

The place cell activity of hippocampal pyramidal cells has been described as the cognitive map substrate of spatial memory. Replay is observed during hippocampal sharp-wave ripple-associated population burst events and is critical for consolidation and recall-guided behaviors. To present, population burst event (PBE) activity has been analyzed as a phenomenon subordinate to the place code. Here, we use hidden Markov models to study PBEs observed during exploration of both linear mazes and open fields. We demonstrate that estimated models are consistent with temporal replay sequences and that the latent states correspond to a spatial map of the environment. Moreover, we demonstrate the identification of hippocampal replay without recourse to the place code, using only PBE model congruence. These results suggest that downstream regions may rely on PBEs to form a substrate for memory. Additionally, by forming models independent of animal behavior, we lay the groundwork for studies of non-spatial memory.

neuroscience↗