@article {67657, title = {Disrupting cortico-cerebellar communication impairs dexterity.}, journal = {eLife}, volume = {10}, year = {2021}, month = {2021 Jul 29}, abstract = {

To control reaching, the nervous system must generate large changes in muscle activation to drive the limb toward the target, and must also make smaller adjustments for precise and accurate behavior. Motor cortex controls the arm through projections to diverse targets across the central nervous system, but it has been challenging to identify the roles of cortical projections to specific targets. Here, we selectively disrupt cortico-cerebellar communication in the mouse by optogenetically stimulating the pontine nuclei in a cued reaching task. This perturbation did not typically block movement initiation, but degraded the precision, accuracy, duration, or success rate of the movement. Correspondingly, cerebellar and cortical activity during movement were largely preserved, but differences in hand velocity between control and stimulation conditions predicted from neural activity were correlated with observed velocity differences. These results suggest that while the total output of motor cortex drives reaching, the cortico-cerebellar loop makes small adjustments that contribute to the successful execution of this dexterous movement.

}, issn = {2050-084X}, doi = {10.7554/eLife.65906}, author = {Guo, Jian-Zhong and Sauerbrei, Britton A and Cohen, Jeremy D and Mischiati, Matteo and Graves, Austin R and Pisanello, Ferruccio and Branson, Kristin M and Hantman, Adam W} } @article {51795, title = {Cortical column and whole-brain imaging with molecular contrast and nanoscale resolution.}, journal = {Science (New York, N.Y.)}, volume = {363}, year = {2019}, month = {2019 Jan 18}, pages = {eaau8302}, abstract = {

Optical and electron microscopy have made tremendous inroads toward understanding the complexity of the brain. However, optical microscopy offers insufficient resolution to reveal subcellular details, and electron microscopy lacks the throughput and molecular contrast to visualize specific molecular constituents over millimeter-scale or larger dimensions. We combined expansion microscopy and lattice light-sheet microscopy to image the nanoscale spatial relationships between proteins across the thickness of the mouse cortex or the entire\ Drosophila\ brain. These included synaptic proteins at dendritic spines, myelination along axons, and presynaptic densities at dopaminergic neurons in every fly brain region. The technology should enable statistically rich, large-scale studies of neural development, sexual dimorphism, degree of stereotypy, and structural correlations to behavior or neural activity, all with molecular contrast.

}, doi = {10.1126/science.aau8302}, author = {Gao, Ruixuan and Asano, Shoh M and Upadhyayula, Srigokul and Pisarev, Igor and Milkie, Daniel E and Liu, Tsung-Li and Singh, Ved and Graves, Austin R and Huynh, Grace H and Zhao, Yongxin and Bogovic, John A and Colonell, Jennifer and Ott, Carolyn M and Zugates, Christopher T and Tappan, Susan and Rodriguez, Alfredo and Mosaliganti, Kishore R and Sheu, Shu-Hsien and Pasolli, H Amalia and et al} } @article {47463, title = {Brain derived neurotrophic factor differentially modulates excitability of two classes of hippocampal output neurons.}, journal = {Journal of Neurophysiology}, volume = {116}, year = {2016}, month = {2016 May 4}, pages = {466-71}, abstract = {

Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampus-dependent learning and memory. Canonically, this has been ascribed to an enhancing effect on neuronal excitability and synaptic plasticity in the CA1 region. However, it is the pyramidal neurons in the subiculum that form the primary efferent pathways conveying hippocampal information to other areas of the brain, and yet the effect of BDNF on these neurons has remained unexplored. We present new data that BDNF regulates neuronal excitability and cellular plasticity in a much more complex manner than previously suggested. Subicular pyramidal neurons can be divided into two major classes, which have different electrophysiological and morphological properties, different requirements for the induction of plasticity and different extra-hippocampal projections. We found that BDNF increases excitability in one class of subicular pyramidal neurons, yet decreases excitability of the other class. Further, while endogenous BDNF was necessary for the induction of synaptic plasticity in both cell types, BDNF enhanced intrinsic plasticity in one class of pyramidal neurons, yet suppressed intrinsic plasticity in the other. Taken together, these data suggest a novel role for BDNF signaling, as it appears to dynamically and bidirectionally regulate the output of hippocampal information to different regions of the brain.

}, issn = {1522-1598}, doi = {10.1152/jn.00186.2016}, author = {Graves, Austin R and Moore, Shannon J and Spruston, Nelson and Tryba, Andrew Kieran and Kaczorowski, Catherine C} } @article {47277, title = {Cortex commands the performance of skilled movement.}, journal = {eLife}, volume = {4}, year = {2015}, month = {2015 Dec 3}, abstract = {

Mammalian cerebral cortex is accepted as being critical for voluntary motor control, but what functions depend on cortex is still unclear. Here we used rapid, reversible optogenetic inhibition to test the role of cortex during a head-fixed task in which mice reach, grab, and eat a food pellet. Sudden cortical inhibition blocked initiation or froze execution of this skilled prehension behavior, but left untrained forelimb movements unaffected. Unexpectedly, kinematically normal prehension occurred immediately after cortical inhibition even during rest periods lacking cue and pellet. This {\textquoteright}rebound{\textquoteright} prehension was only evoked in trained and food-deprived animals, suggesting that a motivation-gated motor engram sufficient to evoke prehension is activated at inhibition{\textquoteright}s end. These results demonstrate the necessity and sufficiency of cortical activity for enacting a learned skill.

}, issn = {2050-084X}, doi = {10.7554/eLife.10774}, author = {Guo, Jian-Zhong and Graves, Austin R and Guo, Wendy W and Zheng, Jihong and Lee, Allen and Rodr{\'\i}guez-Gonz{\'a}lez, Juan and Li, Nuo and Macklin, John J and Phillips, James W and Mensh, Brett D and Branson, Kristin and Hantman, Adam W} } @article {47036, title = {Dopamine is required for the neural representation and control of movement vigor.}, journal = {Cell}, volume = {162}, year = {2015}, month = {2015 Sep 10}, pages = {1418-30}, abstract = {

Progressive depletion of midbrain dopamine neurons (PDD) is associated with deficits in the initiation, speed, and fluidity of voluntary movement. Models of\ basal ganglia function focus on initiation deficits; however, it is unclear how they account for deficits in the speed or amplitude of movement (vigor). Using an effort-based operant conditioning task for head-fixed mice, we discovered distinct functional classes of neurons in the dorsal striatum that represent movement vigor. Mice with PDD exhibited a progressive reduction in vigor, along with a selective impairment of its neural representation in striatum. Restoration of dopaminergic tone with a synthetic precursor ameliorated deficits in movement vigor and its neural representation, while suppression of striatal activity during movement was sufficient to reduce vigor. Thus, dopaminergic input to the dorsal striatum is indispensable for the emergence of striatal activity that mediates adaptive changes in movement vigor. These results suggest refined intervention strategies for Parkinson{\textquoteright}s disease.

}, doi = {10.1016/j.cell.2015.08.014}, author = {Panigrahi, Babita and Martin, Kathleen A and Li, Yi and Graves, Austin R and Vollmer, Alison and Olson, Lars and Mensh, Brett D and Karpova, Alla Y and Dudman, Joshua T} } @article {6720, title = {Hippocampal pyramidal neurons comprise two distinct cell types that are countermodulated by metabotropic receptors.}, journal = {Neuron}, volume = {76}, year = {2012}, month = {2012 Nov 21}, pages = {776-89}, abstract = {

Relating the function of neuronal cell types to information processing and behavior is a central goal of neuroscience. In the hippocampus, pyramidal cells in CA1 and the subiculum process sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information, which they transmit throughout the brain. Do these cells constitute a single class or are there multiple cell types with specialized functions? Using unbiased cluster analysis, we show that there are two morphologically and electrophysiologically distinct principal cell types that carry hippocampal output. We show further that these two cell types are inversely modulated by the synergistic action of glutamate and acetylcholine acting on metabotropic receptors that are central to hippocampal function. Combined with prior connectivity studies, our results support a model of hippocampal processing in which the two pyramidal cell types are predominantly segregated into two parallel pathways that process distinct modalities of information.

}, keywords = {3-dione, 6-Cyano-7-nitroquinoxaline-2, Analysis of Variance, Animals, Benzylamines, Biophysics, CA1 Region, Electric Stimulation, Excitatory Amino Acid Antagonists, Excitatory Amino Acid Transporter 3, GABA Antagonists, Glutamate Decarboxylase, Hippocampal, Lysine, Male, Membrane Potentials, Metabotropic Glutamate, Neurons, Newborn, Patch-Clamp Techniques, Phosphinic Acids, Pyridazines, Rats, Receptors, Time Factors}, issn = {1097-4199}, doi = {10.1016/j.neuron.2012.09.036}, author = {Graves, Austin R and Moore, Shannon J and Bloss, Erik B and Mensh, Brett D and Kath, William L and Spruston, Nelson} }