Biology subjects

Ramirez, A. N.

Publications and source records attributed to Ramirez, A. N..

5 recordsLinked to original sources

bioRxiv2026

Striatal interneuron microcircuits gate reinforcement to stabilize adaptive choice

The dorsomedial striatum guides learning and adaptive decision-making through excitatory synaptic control of its spiny projection neuron outputs. However, the contributions of local inhibitory microcircuitry remain poorly understood. Here, we identify an interneuron circuit in the dorsomedial striatum that links outcome processing to adaptive action selection. During probabilistic push-pull reversal learning, interneurons represented immediate outcomes: somatostatin interneurons were recruited on unrewarded trials and unexpected rewarded trials, whereas tyrosine hydroxylase interneurons were suppressed on unrewarded trials and recruited on rewarded trials. In vivo recruitment of tyrosine hydroxylase interneurons suppressed somatostatin interneuron activity and increased activity in both direct- and indirect-pathway striatal projection neurons, revealing a polysynaptic disinhibitory microcircuit. Transient inhibition of somatostatin interneurons in this pull-tuned region produced a sustained increase in aberrant pull choices and occupancy of a suboptimal pull-preferring behavioral state, whereas inhibition of tyrosine hydroxylase interneurons produced a sustained impairment of pull reinforcement. Longer-term policy changes following somatostatin interneuron inhibition coincided with postsynaptic potentiation of excitatory synapses onto striatal projection neurons, suggesting a potential substrate for the persistence of altered behavioral policies. Together, these findings identify a disinhibitory striatal circuit motif gating reinforcement which transforms individual trial outcomes into temporally broader policy.

neuroscience↗

bioRxiv2026

Comprehensive 3D mapping reveals distinct spatial gradients of SST, PV, and TH interneurons across the mouse caudoputamen

In addition to spatially organized excitatory forebrain inputs along its mediolateral, dorsoventral, and anteroposterior axes, the striatum relies on cellular diversity to subserve its myriad processing functions. Distinct striatal GABAergic interneuron subtypes, including somatostatin (SST), parvalbumin (PV), and tyrosine hydroxylase (TH) interneurons likely subserve complementary computational roles. However, a detailed understanding of how these microcircuit components are distributed across striatal territories remains lacking. To address this gap, we generated a comprehensive three-dimensional atlas of SST, PV, and TH interneurons across the mouse caudoputamen using genetic labeling, brain-wide imaging, and voxel-wise quantification. We found that SST and TH interneurons were relatively enriched in the ventral caudoputamen, whereas PV interneurons were enriched dorsally. In addition, PV and TH interneurons exhibited opposing anteroposterior distribution patterns, with PV interneurons enriched posteriorly and TH interneurons showing a marked decline in density towards the striatal tail. Consequently, while the three interneuron subtypes displayed comparable densities in the functionally defined lateral striatum and anterior ventromedial striatum, PV interneurons predominated in the dorsomedial striatum and tail of striatum. We did not observe major sex differences. Together, these findings reinforce the view that the striatum is not a monolithic structure: in addition to structured excitatory inputs, inhibitory microcircuits themselves are differentially distributed across striatal territories, providing region-specific constraints on circuit computation. By integrating interneuron organization into existing anatomical frameworks, this atlas provides a foundation for linking striatal anatomy to function across behavioral domains.

neuroscience↗

bioRxiv2025

An Open-Source Joystick Platform for Investigating Forelimb Motor Control, Auditory-Motor Integration, and Value-Based Decision-Making in Head-Fixed Mice

Investigation of neural processes underlying motor control requires behavioral readouts that capture the richness of actions, including both categorical (choice-based) information and motor execution (kinematics). We present an open-source platform for behavioral training of head-fixed mice that combines a stationary or retractable forelimb-based joystick, sound-presentation system, capacitive lick sensor, and water reward dispenser. The setup allows for the creation of multiple behavioral paradigms, two of which are highlighted here: a two-alternative forced-choice auditory-motor discrimination paradigm, and a two-armed bandit value-based decision-making task. In the auditory-motor paradigm, mice learn to report high or low frequency tones by pushing or pulling the joystick. In the value-based paradigm, mice learn to push or pull the joystick based on the history of rewarded trials. In addition to reporting categorical choices, this setup provides a rich dataset of motor parameters that reflect components of the underlying learning and decision processes in both of these tasks. These kinematic parameters (including joystick speed and displacement, Frechet similarity of trajectories, tortuosity, angular standard deviation, and movement vigor) provide key additional insights into the motor execution of choices that are not as readily assessed in other paradigms. The systems flexibility of task design, joystick readout, and ease of construction represent an advance compared to currently available manipulandum tasks in mice. We provide detailed schematics for constructing the setup and protocols for behavioral training using both paradigms, with the hope that this open-source resource is readily adopted by neuroscientists interested in mechanisms of sensorimotor integration, motor control, and choice behavior. Significance StatementBehavioral paradigms for experiments in head-restrained mice are important for investigating the relationship between neural activity and behavior. However, behavioral setups are often constrained by high cost, design complexity, and implementation challenges. Here, we present an open-source platform for behavioral training of head-fixed mice using a joystick manipulandum. The setup allows for the creation of multiple behavioral paradigms, including an auditory-motor discrimination paradigm, and a value-based decision-making task. We include detailed instructions for construction and implementation of the entire open-source behavioral platform.

neuroscience↗

bioRxiv2023

Long-term in vivo three-photon imaging reveals region-specific differences in healthy and regenerative oligodendrogenesis

The generation of new myelin-forming oligodendrocytes in the adult CNS is critical for cognitive function and regeneration following injury. Oligodendrogenesis varies between gray and white matter regions suggesting that local cues drive regional differences in myelination and the capacity for regeneration. Yet, the determination of regional variability in oligodendrocyte cell behavior is limited by the inability to monitor the dynamics of oligodendrocytes and their transcriptional subpopulations in white matter of the living brain. Here, we harnessed the superior imaging depth of three-photon microscopy to permit long-term, longitudinal in vivo three-photon imaging of an entire cortical column and underlying subcortical white matter without cellular damage or reactivity. Using this approach, we found that the white matter generated substantially more new oligodendrocytes per volume compared to the gray matter, yet the rate of population growth was proportionally higher in the gray matter. Following demyelination, the white matter had an enhanced population growth that resulted in higher oligodendrocyte replacement compared to the gray matter. Finally, deep cortical layers had pronounced deficits in regenerative oligodendrogenesis and restoration of the MOL5/6-positive oligodendrocyte subpopulation following demyelinating injury. Together, our findings demonstrate that regional microenvironments regulate oligodendrocyte population dynamics and heterogeneity in the healthy and diseased brain.

neuroscience↗

bioRxiv2020

A regulatory program for initiation of Wnt signaling during posterior regeneration

Whole-body regeneration requires the re-establishment of body axes for appropriate patterning of new and old tissue. Wnt signaling has been utilized to correctly regenerate tissues along the primary axis in many animals. However, the causal molecular mechanisms that first launch Wnt signaling during regeneration are poorly characterized. We used the acoel worm Hofstenia miamia to identify processes that initiate Wnt signaling. Transcriptome profiling, in situ hybridization, and functional studies revealed a Wnt ligand, wnt-3, as an early wound-induced gene specifically activated in posterior-facing wound sites and was required for establishing posterior identity during regeneration. wnt-3 was upregulated upon amputation in stem cells, and its inhibition affected stem cell proliferation. Ectopic expression of anterior markers in wnt-3 RNAi head fragments was stem cell dependent. Chromatin accessibility data revealed that wnt-3 activation during regeneration required input from the general wound response. Additionally, the expression of a different Wnt ligand, wnt-1, prior to amputation was required for activation of wound-induced wnt-3 expression. Our study establishes a gene regulatory network for initiating Wnt signaling in posterior tissues in a bilaterian.

developmental biology↗