Biology subjects

McGehee, D. S.

Publications and source records attributed to McGehee, D. S..

3 recordsLinked to original sources

bioRxiv2024

Opposing Motor Memories in the Direct and Indirect Pathways of the Basal Ganglia

Loss of dopamine neurons causes motor deterioration in Parkinsons disease patients. We have previously reported that in addition to acute motor impairment, the impaired motor behavior is encoded into long-term memory in an experience-dependent and task-specific manner, a phenomenon we refer to as aberrant inhibitory motor learning. Although normal motor learning and aberrant inhibitory learning oppose each other and this is manifested in apparent motor performance, in the present study, we found that normal motor memory acquired prior to aberrant inhibitory learning remains preserved in the brain, suggesting the existence of independent storage. To investigate the neuronal circuits underlying these two opposing memories, we took advantage of the RNA-binding protein YTHDF1, an m6A RNA methylation reader involved in the regulation of protein synthesis and learning/memory. Conditional deletion of Ythdf1 in either D1 or D2 receptor-expressing neurons revealed that normal motor memory is stored in the D1 (direct) pathway of the basal ganglia, while inhibitory memory is stored in the D2 (indirect) pathway. Furthermore, fiber photometry recordings of GCaMP signals from striatal D1 (dSPN) and D2 (iSPN) receptor-expressing neurons support the preservation of normal memory in the direct pathway after aberrant inhibitory learning, with activities of dSPN predictive of motor performance. Finally, a computational model based on activities of motor cortical neurons, dSPN and iSPN neurons, and their interactions through the basal ganglia loops supports the above observations. These findings have important implications for novel approaches in treating Parkinsons disease by reactivating preserved normal memory, and in treating hyperkinetic movement disorders such as chorea or tics by erasing aberrant motor memories.

neuroscience↗

bioRxiv2022

PERSISTENT RELIEF OF MOTOR SYMPTOMS IN A PARKINSONIAN MOUSE MODEL AFTER INDUCTION OF LTD AT CORTICAL INPUTS TO INDIRECT PATHWAY STRIATAL NEURONS

In Parkinsons disease (PD) patients, dopamine replacement therapy requires days to reach maximal effects, and the return of symptoms without treatment is similarly delayed. We previously postulated that these phenomena are mediated by plasticity of coritcostriatal synapses. As dopamine depletion is expected to promote aberrant potentiation of the cortical inputs onto indirect pathway neurons, we reasoned that induction of LTD here could reduce motor deficits in a PD model. Optogenetic cortical stimulation combined with a D2 receptor agonist, quinpirole, induces robust optical LTD (oLTD) in brain slices from 6-OHDA lesioned mice. When lesioned mice were subjected to corticostriatal oLTD treatment over 5 days, motor performance was improved for >3 weeks. Consistent with LTD induction, oLTD-treated mice had reduced VGLUT1 expression in striatum and greater excitability of D2 neurons. These findings suggest that reversing aberrant corticostriatal synaptic plasticity in the indirect pathway may lead to persistent relief of PD motor symptoms.

neuroscience↗

bioRxiv2020

Cocaine causes rapid remodeling of dopaminergic axons, synapses, and mitochondria

Dopaminergic (DA) neurons exert profound influences on behavior including addiction. However, how DA axons communicate with target neurons and how those communications change, for example, with drug exposure, remains poorly understood. We combine recent advances in cell type specific labeling for electron microscopy with large volume three-dimensional serial electron microscopy - connectomics- to detail DA connections in the Nucleus Accumbens (NAc) across multiple animals and after exposure to cocaine. We find that DA axonal varicosities are of four general types: 38% are empty, 25% contain few small ([~]50 nm diameter) vesicles, 19% contain few large ([~]133 nm diameter) vesicles, and 18% have mixed small and large vesicles, suggesting that DA axons may use multiple types of neurotransmitters. Individual DA axons were significantly more likely to contain multiple varicosities of the same type relative to chance, suggesting a new method of DA axon classification. Across all categories, we find only rare examples (<2%, 6/410) of varicosities making specific synapses with any neighboring neuron with the few examples being made exclusively on the shafts and soma of resident NAc neurons. Instead, we find much more frequently (15%) that DA varicosities form spinule-like structures: physical membrane interdigitations with nearby dendrites or excitatory and inhibitory axons. Days after a brief exposure to cocaine, DA axons were extensively branched relative to controls but with similar densities of varicosities and spinules. Additionally, cocaine exposure results in the formation of blind-ended "bulbs" in DA axons, filled with mitochondria, and reminiscent of axonal retraction in the developing and damaged brain. Every bulb was surrounded by elaborated glia further suggestive of active remodeling. Finally, mitochondrial lengths increased by [~]2.2 times relative to control throughout DA axons and NAc spiny dendrites after cocaine exposure but not in DA soma or DA dendrites. We conclude that DA axonal transmission is unlikely to be mediated via classical synapses in the NAc and that the major locus of anatomical plasticity of DA circuits after exposure to cocaine are large scale axonal rearrangements with correlated changes in mitochondria.

neuroscience↗