Biology subjects

Bartlett, M. J.

Publications and source records attributed to Bartlett, M. J..

11 recordsLinked to original sources

bioRxiv2026

The anti-dyskinetic and the anti-parkinsonian effects of sub-anesthetic ketamine are also present in female preclinical models

Biological sex is an important determinant of neuropharmacological response, yet females remain underrepresented in preclinical studies of Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). We previously demonstrated that sub-anesthetic ketamine reduces established LID, attenuates dyskinesia development, and produces anti-parkinsonian effects in male unilateral 6-hydroxydopamine (6-OHDA) rat models. However, whether these therapeutic effects extend to females remained unknown. Here, we evaluated the anti-dyskinetic and anti-parkinsonian effects of sub-anesthetic ketamine in female Sprague-Dawley rats using the attenuation and established models of LID. In the attenuation paradigm, unilateral 6-OHDA-lesioned females received repeated L-DOPA administration with either ketamine (20 mg/kg, i.p.; 10-h dosing paradigm) or vehicle. Ketamine significantly attenuated the progressive development of dyskinesia, indicating that early intervention modified the trajectory of LID expression. In the established LID paradigm, ketamine produced robust significant acute reductions in abnormal involuntary movements (AIMs) after dyskinesia had fully developed, and these significant effects persisted for up to 49 days following treatment, demonstrating sustained suppression of dyskinesia severity. To determine whether ketamine altered therapeutic motor function, forelimb adjusting steps testing was performed in female unilateral 6-OHDA rats. Ketamine did not impair L-DOPA-mediated motor improvement suggesting compatibility with the gold standard medication. Ketamine was also by itself associated with significantly improved stepping performance during ketamine treatment conditions, indicating acute anti-parkinsonian motor benefit. Together, these findings demonstrate that the anti-dyskinetic and anti-parkinsonian effects of ketamine extend to female preclinical models and strengthen the translational rationale for repurposing sub-anesthetic ketamine as a potential therapeutic strategy for individuals with LID.

neuroscience↗

bioRxiv2026

Dyskinesia induced by a dopamine 2 receptor-like agonist, but not a dopamine 1 receptor-like agonist, is blocked by sub-anesthetic ketamine

L-DOPA remains the most effective symptomatic treatment for Parkinson's disease, but chronic administration is frequently complicated by L-DOPA-induced dyskinesia (LID). Our prior work has established that sub-anesthetic ketamine can reduced LID acutely and has a long-lasting neuroplastic effect. This study tested whether low-dose ketamine reduces dyskinesia induced specifically by dopamine D2R-like or D1R-like receptor activation. Male Sprague Dawley rats were primed with daily L-DOPA to establish dyskinesia and then challenged with quinpirole, a D2R-like receptor agonist, or SKF-81297, a D1R-like receptor agonist, to induce abnormal involuntary movements (AIMs). After stable AIM baselines were established, animals received agonist plus vehicle or agonist plus ketamine. Limb, axial, and orolingual AIMs were scored on the acute treatment day (D0) and after washout on D4 and D7. Quinpirole and SKF-81297 reliably produced stable total LAO AIM scores following L-DOPA priming. Ketamine significantly reduced only quinpirole-induced, but not SKF-81297-induced, total AIMs compared with vehicle on D0, demonstrating an acute anti-dyskinetic effect. This reduction persisted after washout, with ketamine-treated animals continuing to show significantly lower AIMs on D4 and D7. Time-course analyses further showed reduced AIMs expression across the post-quinpirole observation period on D0 and at multiple time points on D7. These findings demonstrate that ketamine suppresses quinpirole-induced dyskinesia in L-DOPA-primed male rats and suggest that D2R-like receptor-mediated or indirect pathway-related mechanisms, but not direct pathway-related mechanisms, may contribute to ketamine's anti-dyskinetic effects. Together, these results extend prior work on ketamine by linking its sustained anti-dyskinetic effects to dyskinesia driven by D2R-like receptor stimulation in vivo.

neuroscience↗

bioRxiv2026

Neuroprotective activity of sub-anesthetic ketamine in a preclinical model of Parkinson's disease is not blocked by antagonizing brain-derived neurotrophic factor signaling

Treatment with low-dose ketamine is neuroprotective in rodent models of acute damage, while high doses of ketamine can be neurotoxic. Our group has previously shown that sub-anesthetic ketamine treatment leads to long-term reduction of L-DOPA-induced dyskinesia (LID) via brain-derived neurotrophic factor (BDNF)-signaling in a rat 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD). In this report, we investigated if sub-anesthetic ketamine is also neuroprotective in a progressive 6-OHDA model of PD via neurotrophic action through the tropomyosin receptor kinase B (TrkB) receptor. We demonstrated that ketamine-treatment (20 mg/kg, i.p.) prior to striatal administration of the neurotoxin 6-OHDA is neuroprotective, providing near complete protection against development of parkinsonian motor deficits. This robust behavioral efficacy occurred in the presence of only modest preservation of tyrosine hydroxylase (TH) striatal levels (~50-60% loss). Interestingly, based on data from an additional cohort treated with ketamine and ANA-12 (TrkB antagonist) we found that the neuroprotective effects of ketamine are not mediated by TrkB receptors. Semi-quantitative western analysis showed that the relative tyrosine hydroxylase content in the striatum was not significantly increased in ketamine-treated rats compared to vehicle. Unbiased stereology of dopamine neurons in the substantia nigra pars compacta (SNc) revealed no significant differences between any of the groups. The role of BDNF was evaluated with in situ hybridization for RNA of BDNF and TrkB. While BDNF expression was not changed, co-administration of ketamine and ANA-12 led to a significant decrease in TrkB receptor expression compared to ketamine-only on the lesioned but not the intact hemisphere in the SNc. In conclusion, we show that ketamine at the low dose currently pursued for therapeutic benefit for LID led to robust behavioral motor improvement in this rodent PD degeneration model, yet these protective effects were not driven by neurotrophic BDNF-signaling, indicating complex mechanisms are underlying neuroprotective activities of low-dose ketamine.

neuroscience↗

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↗

bioRxiv2025

Early intervention with a PACAP lactoside following repetitive mild traumatic brain injury prevents persistent LHb hyperactivity and motivational deficits in male mice

Mild traumatic brain injury (mTBI) often leads to long-lasting mood disorders and motivational deficits, significantly decreasing quality of life. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has known neuroprotective effects and is often deficient in neurological conditions, but its role in preventing mTBI's long-term effects on mood circuits remains unclear. Our previous studies of repetitive closed-head mTBI in murine models found that the lateral habenula (LHb) is a key area for post-injury impairments. These impairments are characterized by mTBI-induced LHb hyperactivity and mood-related behavioral deficits. Here we investigated if a novel PACAP type I receptor (PAC1R) agonist, TES2320, could prevent or treat these long-term mTBI effects. The drug is based on a truncated glycoside analogue of PACAP that is stable and brain penetrant. Using RNAscope, we first found that mTBI caused a persistent and widespread reduction in PACAP mRNA within the LHb, suggesting a possible mTBI-related PACAP signaling deficiency in LHb circuits. We then used two intervention strategies in young adult male mice: an early intervention administered immediately after injury and a late intervention given as a single injection one-month post-injury. One month after injury, we measured LHb activity and self-care grooming motivation. Both early and late PAC1 agonist interventions almost completely normalized the mTBI-induced increases in LHb spontaneous tonic activity and hyperexcitability. However, only the early intervention improved the delayed initiation of grooming seen in mTBI mice. Unfortunately, a single late PAC1R agonist injection not only failed to reverse the grooming delay, but also significantly reduced total grooming behavior 24 hours after treatment. This finding points to a potential behavioral side effect of late PAC1R agonist administration on grooming. Overall, our findings confirm that an early PAC1R agonist intervention effectively prevents mTBI-induced LHb hyperactivity and associated motivational deficits, likely by restoring the persistent PACAP signaling deficiency in the LHb and its related circuits. This preclinical study provides strong evidence that novel PAC1R agonists could be a valuable preventive therapy for mTBI-related depression and anti-reward circuit dysfunction.

neuroscience↗

bioRxiv2025

Manual lymph drainage massage of the head and neck improves cognition and reduces pathological biomarkers in the 5x-FAD mouse model of Alzheimers disease

Alzheimers disease (AD) affects 6.9 million people over the age of 65 in the US and is expected to double by 2060. While FDA approved immunotherapies slow cognitive decline in some individuals with AD, they do not improve cognition, are costly, and have significant side-effects. Therefore, new targets, approaches, and treatments for AD are a necessity. There are no FDA approved therapies for AD that target the brains lymphatic system. It is well established that the toxic protein, amyloid-beta (A{beta}), accumulates in the AD brain. Recent studies have shown that A{beta} is cleared via interstitial fluid and cerebrospinal fluid through a pathway involving the glymphatic system--meningeal lymphatic vessels--leading to deep and superficial cervical lymphatic vessels and nodes. Therefore, any blockage along this route can cause inefficient drainage and result in pathological buildup of A{beta}, which can lead to AD. Here, we propose a new approach to treating AD by manual lymph drainage (MLD), which is a light skin massage traditionally used to reduce fluid accumulation in lymphedema. This therapy has also been demonstrated to be safe in individuals with AD, but its effects on cognition and biomarkers of AD has never been investigated. In this study we demonstrate that repeated MLD of the head and neck, including the superficial cervical lymphatic vessels (scLVs), improves cognitive function in AD as measured in both the Y-maze and nest-building tests. We also show that this coincides with a reduction in plasma levels of neurofilament light chain (NfL), a non-specific biomarker for neuronal cell death and axonal damage. MLD was also shown to reduce A{beta} in the hippocampus of these mice. Combined, this data provides compelling proof-of-principle evidence for the potential of MLD as a standalone or adjunct therapy in the treatment of AD.

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

Antagonism of kappa opioid receptors worsens the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion

Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinsons disease (PD) and following the development of L-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of L-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of L-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg L-DOPA doses. However, after reaching the 72 mg/kg L-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of L-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI. HighlightsO_LIMild L-DOPA-induced dyskinesia develops in moderately lesioned parkinsonian rats C_LIO_LIIn the moderately-lesioned dorsolateral striatum tonic dopamine is increased C_LIO_LIAntagonizing dynorphin does not affect parkinsonian motor symptoms in rodents C_LIO_LIAntagonizing dynorphin increases rate of development of L-DOPA-induced dyskinesia C_LIO_LITonic dopamine in dorsolateral striatum is unchanged after antagonizing dynorphin C_LI

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↗