Biology subjects

Cowen, S. L.

Publications and source records attributed to Cowen, S. L..

8 recordsLinked to original sources

bioRxiv2026

L-DOPA Rescues Reach Height but Not Trajectory Area in a Bimanual String-Pulling Behavior in Parkinsonian Rats

While gross motor changes in Parkinson's disease, bradykinesia, hypokinesia, difficulty initiating movement, have been well studied in rodent models of the disease, limb movements, and especially bimanual coordination deficits, are more difficult to study in these animal models. Here we describe a novel bimanual string-pulling task that can be used to generate a rich repertoire of behaviors that require limb and bimanual coordination in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion. We show that 6-OHDA lesion significantly reduces string speed, pulling bout duration, paw speed especially during reaching, and reduces the area of paw trajectories during pulling. However, it does not affect the variability around that movement trajectory. We also show that levodopa (L-DOPA) treatment restores many of these measures but not all. L-DOPA restores paw speed and string-pulling speed and fully restores paw reach height and pulling bout duration, but has no effect on trajectory area. Together, our results demonstrate that dopamine depletion differentially effects features of this bimanual coordination task, that L-DOPA mostly, but not fully, restores string pulling performance, and opens up a new avenue for measuring the effect of Parkinson's disease treatments on motor movement, allowing for better assessment of how effectively treatments restore motor activity.

neuroscience↗

bioRxiv2026

Hippocampus-evoked polysynaptic responses in the medial prefrontal cortex are attenuated in aged rats.

The hippocampus-medial prefrontal cortex (mPFC) circuit is critical for spatial working memory and decision-making. Age-associated changes to these functions are attributed to alterations in this circuit, although the exact mechanisms remain unclear. These regions are connected via monosynaptic projections from the intermediate (iHC) and ventral (vHC) hippocampus to the infralimbic (IL) and prelimbic (PL) regions of the mPFC. We examined the functional connection between these regions in young (10-12 months) and aged (23-26 months) male F344 rats. High-density Neuropixels probes were used to record mPFC field potentials (fEPSPs) and single-unit responses to electrical stimulation of iHC and vHC. We observed that hippocampal stimulation evoked both short-latency (5-35 ms) monosynaptic and long-latency (35-100 ms) polysynaptic responses in PL and IL cortices. Monosynaptic responses, reflecting direct hippocampal-prefrontal synaptic transmission, had lower vHC-evoked IL fEPSP amplitude in aged rats, while other subregional HC-mPFC connections and evoked neural firing were preserved. The polysynaptic responses, reflecting local mPFC circuit recruitment, also had lower IL fEPSP amplitude in aged rats, while evoked neural firing in the polysynaptic window was diminished in both mPFC regions. Age-associated polysynaptic changes in mPFC neural responses differed by the HC stimulation site. In aged rats, iHC stimulation resulted in a lower proportion of recruited neurons, while vHC stimulation resulted in diminished evoked mPFC firing rates, compared to young rats. Our findings demonstrate that aging selectively impairs vHC-mPFC direct synaptic transmission and mPFC local responses, with infralimbic circuits showing particular vulnerability. These circuit-level deficits may contribute to age-related impairments in cognitive flexibility. Significance StatementAging impairs spatial working memory and decision making which require hippocampus-prefrontal communication. We examined the age-related changes in the functional connection of the intermediate (iHC) and ventral (vHC) hippocampus direct projection onto prelimbic (PL) and infralimbic (IL) regions of the mPFC. We found the vHC-evoked IL monosynaptic excitatory field potential amplitude was lower in aged rats, while other HC-mPFC connections were preserved. The evoked polysynaptic excitatory field potentials and single-unit responses were attenuated with age in both mPFC regions with responses differing between HC stimulation sites. These results identify subregional changes in how hippocampal inputs alter mPFC local recruitment in aging that may explain related impairments in cognitive flexibility.

neuroscience↗

bioRxiv2025

Alpha-synuclein overexpression reduces neural activity within a basal ganglia vocal nucleus in a zebra finch model

Changes in vocal pitch, loudness, and timing are prevalent in Parkinsons Disease (PD) and a target for early intervention and treatment. The neural mechanisms underlying these impairments are not understood, motivating work in animal models. The adult male zebra finch songbird is uniquely poised for these studies given vocally-dedicated brain nuclei and a quantifiable output (birdsong). Our prior publication revealed that injection of an adeno-associated virus (AAV5) expressing the human (h) alpha-synuclein (hSNCA, a-syn) gene into basal ganglia vocal nucleus Area X results in elevated insoluble a-syn protein and parkinsonian-like changes including softer, shorter, and reduced vocalizations compared to controls. Here, we test the hypothesis that AAV-hSNCA overexpression reduces the firing rate of specific neuronal sub-types in Area X using in vivo recordings in anesthetized finches. Five classes of neurons were differentiated in AAV-treated finches based on waveform width (narrow vs. wide) and firing rates (low vs. fast). Wide-waveform/low-rate activity is a consistent feature of striatal medium spiny neurons (MSNs), a dominant cell type in Area X and in mammalian basal ganglia. Reduced firing rates and enhanced post-peak rebound were detected in the AAV-hSNCA group for putative MSN neurons compared to AAV controls. No differences in firing rate nor waveform shape were detected for the narrow waveform neurons. Our findings provide the first characterization of early a-syn-driven neural activity changes in vocal control neurocircuitry.

neuroscience↗

bioRxiv2025

Opposing responses of hippocampal theta oscillations to running and a forelimb-dominated sensorimotor behavior

Hippocampal theta oscillations regulate the timing of neurons to support navigation, memory formation, and sensorimotor integration. Theta is modulated by running speed, breathing, whisking, and jumping and increases in tasks involving memory encoding or retrieval. The positive relationship between theta frequency and running speed is believed stabilize hippocampal representations of space amid movement variability. Here, we incorporated a novel string-pulling task to determine if established relationships between movement and theta hold when progress to a reward is determined by the length of string pulled. This task eliminates many speed-associated inputs, such vestibular, visual, and hindlimb information, and allows an unprecedented level of precision in the analysis of individual paw movements. Given that animals move the string a fixed length to acquire a reward, we predicted that the positive relationship between theta frequency and speed would hold. ApproachFive Sprague Dawley rats (4 mo.) were trained to continuously pull a string a fixed distance of 208 cm using an automated string-pulling system and run on a track for food reward. Local-field data was acquired from electrodes in dorsal CA1. ResultsRelationships between theta and movement speed were distinct during string pulling and running. While theta was robust in both conditions, frequency was significantly reduced during string-pulling and showed no speed-frequency coupling, unlike running. This difference could result from the conflict between hindlimb and forelimb signals, with only forelimb movement signaling advancement. Fine-grained analysis of paw movements during string-pulling (lift, advance, grasp, pull, push) revealed that theta power and frequency peaked during the contralateral paws downward push despite paw speed being low during this action. This suggests that theta frequency and power could respond to effort rather than purely kinematic information. Notably, running-associated theta may similarly reflect both speed and effort as most locomotor tasks conflate these variables. Finally, theta phase aligned from one reach-pull cycle to the next during the downward pull motion - the first action that directly advances the string forward. Since phase-locking has been associated with sensorimotor gating, synchrony at this point could reflect the gating of inputs that are the most causally relevant for reaching the reward, potentially facilitating integration of action-outcome signals for memory encoding and navigation. Taken together, these data support a dual-scale view of hippocampal processing and theta-band activity where macroscale theta activity requires suprathreshold sensory, vestibular, and proprioceptive drive and microscale theta remains sensitive to subsecond limb movements.

neuroscience↗

bioRxiv2024

Differential effects of statins on the anti-dyskinetic activity of sub-anesthetic ketamine

Sub-anesthetic ketamine has been demonstrated to reduce abnormal involuntary movements (AIMs) in preclinical models of L-DOPA-induced dyskinesia (LID) and retrospective Parkinsons disease case reports. In this study, we examined the effects on L-DOPA-induced dyskinesia of two statins alone and in combination with ketamine in unilateral 6-hydroxydopamine-lesioned male rats, the standard preclinical LID model. Sub-anesthetic ketamine attenuated the development of AIMs, while lovastatin only showed anti-dyskinetic activity at the beginning of the priming but did not prevent the development of LID. The polar pravastatin blocked the long-term anti-dyskinetic effects of ketamine, while the non-polar lovastatin did not. This study shows different classes of statins affect LID differentially, points to an important drug interaction and further supports ongoing clinical testing of sub-anesthetic ketamine to treat LID in individuals with Parkinsons disease.

neuroscience↗

bioRxiv2023

Automated system for training and assessing string-pulling behaviors in rodents

String-pulling tasks have been used for centuries to study coordinated bimanual motor behavior and problem solving. String pulling is rapidly learned, ethologically grounded, and has been applied to many species and disease conditions. Typically, training of string-pulling behaviors is achieved through manual shaping and baiting. Furthermore, behavioral assessment of reaching, grasping, and pulling is often performed through labor intensive manual video scoring. No system, to our knowledge, currently exists for the automated shaping and assessment of string-pulling behaviors. Here we describe the PANDA system (Pulling And Neural Data Analysis), an inexpensive hardware and software system that utilizes a continuous string loop connected to a rotary encoder, feeder, microcontroller, high-speed camera, and analysis software for assessment and training of string-pulling behaviors and synchronization with neural recording data. We demonstrate this system in unimplanted rats and rats implanted with electrodes in motor cortex and hippocampus and show how the PANDA system can be used to assess relationships between paw movements and single-unit and local-field activity. We also found that automating the shaping procedure significantly improved overall performance, with rats regularly pulling >100 meters during a 15-minute session. In conclusion, the PANDA system will be of general use to researchers investigating motor control, motivation, and motor disorders such as Parkinsons disease, Huntingtons disease, and stroke. It will also support the investigation of neural mechanisms involved in sensorimotor integration. HighlightsO_LIHigh-speed tracking of continuous grasping and pulling behaviors. C_LIO_LIAutomated and adaptive reinforcement of string-pulling behavior. C_LIO_LIIntegration with neural recording and video tracking systems. C_LIO_LIOpen-source software and hardware. C_LI Supplemental FilesThe supplemental pdf contains additional designs and behavioral data and has been uploaded. Source code and 3D and laser cut design files can be found at: https://github.com/CowenLab/String_Pulling_System/ Videos are in the GitHub repository at: https://github.com/CowenLab/String_Pulling_System/tree/main/Videos

bioengineering↗

bioRxiv2022

Heterogeneous patterns of ventral tegmental area neuronal activity coordinate nucleus accumbens dopamine release

Dopamine release in the ventral striatum is fundamental to adaptive appetitive behavior. Frustratingly, technological, and methodological hurdles have limited the investigation of the mechanisms that drive phasic dopamine release. Although dopamine neuron activation in the ventral tegmental area (VTA) surely results in dopamine release, how populations of these neurons coordinate their activities in time to modulate the temporal pattern of release remains unclear. Additionally, burgeoning evidence suggests that control over striatal dopamine release is not solely regulated by the burst firing of VTA neurons or even cell-body activation of these neurons. Here, we recorded VTA neurons while simultaneously monitoring pharmacologically induced phasic dopamine release events in the ventral striatum (nucleus accumbens core) of anesthetized rats. On average, dopaminergic and non-dopaminergic neurons increased activity at the time of the onset of release and decreased at the time of peak release; however, the tuning of individual VTA neurons to dopamine release was notably heterogenous, with subsets of neurons responding prior to release, at release onset, or during release. Other neurons were notably silent during release but active otherwise. Interestingly, both putative dopaminergic and non-dopaminergic neurons expressed this temporally heterogeneous response pattern. Furthermore, the firing activity of dopaminergic, but not non-dopaminergic neurons, correlated with the magnitude of dopamine release. These data suggest that populations of VTA neurons become active at distinct times of a dopamine release event to sculpt the temporal pattern of release.

neuroscience↗

bioRxiv2020

Spectral Signatures of L-DOPA-Induced Dyskinesia Depend on L-DOPA Dose and are Suppressed by Ketamine

L-DOPA-induced dyskinesias (LID) are debilitating motor symptoms of dopamine-replacement therapy for Parkinsons disease (PD) that emerge after years of L-DOPA treatment. While there is an abundance of research into the cellular and synaptic origins of LID, less is known about how LID impacts systems-level circuits and neural synchrony, how synchrony is affected by the dose and duration of L-DOPA exposure, or how potential novel treatments for LID, such as sub-anesthetic ketamine, alter this activity. Sub-anesthetic ketamine treatments have recently been shown to reduce LID, and ketamine is known to affect neural synchrony. To investigate these questions, we measured movement and local-field potential (LFP) activity from the motor cortex (M1) and the striatum of preclinical rodent models of PD and LID. In the first experiment, we investigated the effect of the LID priming procedures and L-DOPA dose on neural signatures of LID. Two common priming procedures were compared: a high-dose procedure that exposed unilateral 6-hydroxydopamine-lesioned rats to 12 mg/kg L-DOPA for 7 days, and a low-dose procedure that exposed rats to 7 mg/kg L-DOPA for 21 days. Consistent with reports from other groups, 12 mg/kg L-DOPA triggered LID and 80-Hz oscillations; however, these 80-Hz oscillations were not observed after 7 mg/kg administration despite clear evidence of LID, indicating that 80-Hz oscillations are not an exclusive signature of LID. We also found that weeks-long low-dose priming resulted in the emergence of non-oscillatory broadband gamma activity (> 30 Hz) in the striatum and theta-to-high-gamma cross-frequency coupling (CFC) in M1. In a second set of experiments, we investigated how ketamine exposure affects spectral signatures of low-dose L-DOPA priming. During each neural recording session, ketamine was delivered through 5 injections (20 mg/kg, i.p.) administered every 2 hours. We found that ketamine exposure suppressed striatal broadband gamma associated with LID but enhanced M1 broadband activity. We also found that M1 theta-to-high-gamma CFC associated with the LID on-state was suppressed by ketamine. These results suggest that ketamines therapeutic effects are region specific. Our findings also have clinical implications, as we are the first to report novel oscillatory signatures of the common low-dose LID priming procedure that more closely models dopamine replacement therapy in individuals with PD. We also identify neural correlates of the anti-dyskinetic activity of sub-anesthetic ketamine treatment.

pathology↗