Biology subjects

Wichmann, T.

Publications and source records attributed to Wichmann, T..

6 recordsLinked to original sources

bioRxiv2026

Caudate nucleus aging and its association with brain disorders

The caudate nucleus supports cognition and goal-directed behavior, undergoes age-associated changes, and is implicated in substance use, psychiatric, and neurodegenerative disorders. However, how aging alters its diverse cell types and how such changes relate to diseases remains poorly understood. To address these questions, we assembled single nucleus transcriptomic atlases of the caudate tissue, comprising 963,842 nuclei from 178 human donors, including controls and individuals with alcohol use disorder (AUD) or opioid use disorder (OUD), and 83,699 nuclei from six healthy rhesus macaques. We also curated 3,139 bulk RNA-seq profiles from the caudate and other brain regions spanning controls and multiple diagnostic groups, as well as paired RNA and chromatin accessibility profiles from 257,524 caudate nuclei across 161 control and AUD donors. These datasets enabled comparisons across age, species, brain regions, and diagnostic groups. We found shared glial aging features in humans and macaques, whereas neuronal changes were more divergent. Inferred neuron-to-neuron communication declined with age, with greater declines in AUD. Both transcriptional and chromatin accessibility profiles showed nonlinear age-associated patterns, with pronounced changes in later adulthood. In donors with AUD, age-associated changes appeared earlier, with altered trajectories in lipid metabolism, mitochondrial function, and neuronal signaling. Across comparisons involving AUD, OUD, bipolar disorder, schizophrenia, and Alzheimer disease, mitochondrial function and fatty acid metabolism emerged as consensus features linking caudate aging to diseases, although the direction and extent of overlap varied by disorder and brain region. Together, these findings define cellular and regulatory features of primate caudate aging and reveal shared and context-dependent relationships between aging and brain disorders.

neuroscience↗

bioRxiv2026

Emergence of Task-Related Motor Cortical Dysfunction in Mice with Progressive Parkinsonism

There are substantial functional changes in the primary motor cortex (M1) in Parkinsons disease (PD). However, the temporal relationship between midbrain dopaminergic (DA) neurodegeneration, M1 circuit dysfunction, and Parkinsonian motor symptoms remains poorly understood. Using a genetic mouse model of progressive nigrostriatal DA degeneration ("MitoPark" mice), we determine the time course of M1 cellular dysfunction and skilled movement impairment as the midbrain DA neurons gradually degenerate. M1 pyramidal neuronal subtypes were identified using AAV-mediated retrograde labeling. During progressive DA loss, MitoPark mice developed gradually impaired performance in a reach-to-grasp single-food-pellet task. These impairments were detectable at a moderate motor stage of Parkinsonism. In vivo GCaMP6f imaging revealed that impaired skilled movement was associated with reduced cellular activity and movement responsiveness of M1 pyramidal neurons at a moderate motor stage of Parkinsonism. While both the corticospinal (CSp) and intratelencephalic (IT) neurons send glutamatergic inputs to the striatum, only the CSp neurons showed a selective and significant reduction in cellular activity and movement responsiveness during reaches. At the population level, we found that M1 pyramidal neurons include heterogeneous functional clusters with distinct temporal profiles in response to skilled movement. While movement encoding by different functional clusters is longitudinally stable in control mice, it degrades and diverges significantly in MitoPark mice. The impaired stability is further supported by a longitudinal analysis of individual neuronal activity related to movements. Together, these results provide novel insights into the emergence of M1 circuit pathophysiology at cellular and neural population levels during progressive Parkinsonism.

neuroscience↗

bioRxiv2024

MICROENDOSCOPIC CALCIUM IMAGING IN SUPPLEMENTARY MOTOR AREA AND PRIMARY MOTOR CORTEX OF RHESUS MACAQUES AT REST AND DURING ARM MOVEMENT

The study of motor cortices in non-human primates is relevant to our understanding of human motor control, both in healthy conditions and in movement disorders. Calcium imaging and miniature microscopes allow the study of multiple genetically identified neurons with excellent spatial resolution. We used this method to examine activity patterns of projection neurons in deep layers of the supplementary motor (SMA) and primary motor areas (M1) in four rhesus macaques. We implanted gradient index lenses and expressed GCaMP6f to image calcium transients while the animals were at rest or engaged in an arm reaching task. We tracked the activity of SMA and M1 neurons across conditions, examined cell pairs for synchronous activity, and assessed whether SMA and M1 neuronal activation followed specific sequential activation patterns. We demonstrate the value of in vivo calcium imaging for studying patterns of activity in groups of corticofugal neurons in SMA and M1. HIGHLIGHTSO_LIUse of one-photon miniature microscopes and microendoscopic calcium imaging to study the activity of cortical projection neurons in the supplementary motor area (SMA) and primary motor cortex (M1) of rhesus macaques at rest or performing simple arm reaches. C_LIO_LICalcium transients were related to arm reaches and showed directional sensitivity in a proportion of cells in SMA and M1. C_LIO_LISubsets of cell pairs showed coactivation in SMA and M1 during rest and reaching tasks. The strength of coactivity was not related to the distance between cells. C_LIO_LISMA and M1 neurons displayed sequential activation patterns. C_LIO_LIWe demonstrated that microendoscopic calcium imaging can be used to assess dynamic activity within genetically identified cell populations in deep layers of SMA and M1. C_LI

neuroscience↗

bioRxiv2024

Decreased cellular excitability of pyramidal tract neurons in primary motor cortex leads to paradoxically increased network activity in simulated parkinsonian motor cortex

Primary motor cortex (M1) layer 5B pyramidal tract (PT5B) neurons develop intrinsic pathology in rodent and primate Parkinsons disease (PD) models. We used computer simulation to predict how decreased PT5B neuron excitability, identified with current injection in vitro, would change activity patterns of the M1 network. Using NEURON/NetPyNE, we implemented computer simulations of PT5B neurons based on control and 6-OHDA-treated mouse slice data. Parkinsonian PT5B neurons, in an otherwise unmodified simulated M1 network, produced major changes in LFP oscillatory power: an order of magnitude increase in beta band power around 15 Hz in the rest state. This demonstrated that relatively small changes in PT5B neuron excitability would alter oscillatory patterns of activity throughout the M1 circuit, increasing beta band power, a signature of PD pathophysiology. Dysfunction in PT5B neurons, the final-common-pathway to brainstem and spinal cord, provides a new target to treat PD motor symptoms.

neuroscience↗

bioRxiv2022

Basal Ganglia Neurons in Healthy and Parkinsonian Primates Generate Recurring Sequences of Spikes

The spiking activity of basal ganglia neurons can be characterized by summary statistics such as the average firing rate, or by measures of firing patterns, such as burst discharges, or oscillatory fluctuations of firing rates. Many of these features are altered by the presence of parkinsonism. This study examined another distinct attribute of firing activity, i.e., the occurrence of repeating sequences of inter-spike intervals. We studied this feature in extracellular electrophysiologic recordings that were made in the basal ganglia of Rhesus monkeys, before and after they had been rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phyl-1,2,3,6-tetrahydropyridine (MPTP). Neurons in both pallidal segments and in the subthalamic nucleus tended to fire in repeating sequences, typically 2 ISIs long (i.e., involving three spikes). In recordings that were 5000 inter-spike intervals long, 20-40% of spikes participated in one of many sequences with each ISI replicating the sequence pattern with a timing error of [≤]1%. Compared to similar analyses in shuffled representations of the same data, sequences were more common in the original representation of ISIs in the subthalamic nucleus and the external pallidal segment. Induction of parkinsonism reduced the proportion of sequence spikes in the external pallidum but increased it in the subthalamic nucleus. We found no relation between the sequence generation and the firing rate of neurons, and, at most, a weak correlation between sequence generation and the incidence of bursts. We conclude that basal ganglia neurons fire in recognizable sequences of ISIs, whose incidence is influenced by the induction of parkinsonism.

neuroscience↗

bioRxiv2022

Characterization of ultrapotent chemogenetic ligands for research applications in non-human primates

Chemogenetics is a technique for obtaining selective pharmacological control over a cell population by expressing an engineered receptor that is selectively activated by an exogenously administered ligand. A promising approach for neuronal modulation involves the use of "Pharmacologically Selective Actuator Modules" (PSAMs); these chemogenetic receptors are selectively activated by ultrapotent "Pharmacologically Selective Effector Molecules" (uPSEMs). To extend the use of PSAM/PSEMs to studies in nonhuman primates it is necessary to thoroughly characterize the efficacy and safety of these tools. We describe the time course and brain penetrance in rhesus monkeys of two compounds with promising binding specificity and efficacy profiles in in vitro studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus macaques received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817(0.064 mg/kg) or uPSEM792 (0.87 mg/kg) and plasma and CSF samples were collected over the course of 48 hours. Both compounds exhibited good brain penetrance, relatively slow washout and negligible conversion to potential metabolites - varenicline or hydroxyvarenicline. In addition, we found that neither of these uPSEMs significantly altered heart rate or sleep. Our results indicate that both compounds are suitable candidates for neuroscience studies using PSAMs in nonhuman primates.

neuroscience↗