Biology subjects

Hooks, B. M.

Publications and source records attributed to Hooks, B. M..

9 recordsLinked to original sources

bioRxiv2024

Cell Type Specific Enhancers for Dorsolateral Prefrontal Cortex.

The dorsolateral prefrontal cortex (DLPFC) is crucial to primate cognitive functions, but a paucity of cell type specific tools limits studies of DLPFC neurocomputational principles. Therefore, we set out to identify enhancers that fit inside Adeno-Associated Virus (AAV) vectors and that elicited functional, cell type specific gene expression in the non-human primate (NHP) DLPFC. We used single nucleus RNA-Seq and ATAC-Seq from rhesus macaque tissue samples to define DLPFC cell types and their associated open chromatin regions (OCRs). We trained machine learning (ML) models to recognize the unique regulatory grammar associated with each DLPFC neuron type, performed in silico screening of all OCRs, and identified candidate enhancers most likely to elicit cell type specific transgene expression in each neuron type. For layer 3 pyramidal neurons (L3PNs) and layer 5 extratelencephalic neurons (L5ETs), we cloned the top twelve identified candidates into AAVs and injected them into NHP DLPFC. In situ observation of enhancer-driven expression revealed the best performers, RMacL3-01 and RMacL5ET-01. We validated RMacL3-01 and RMacL5ET-01 using one-at-a-time injections in NHP DLPFC. RMacL3-01 restricted GFP expression to pyramidal neurons in layers 2 and 3, whereas RMacL5ET-01 restricted expression to POU3F1+ neurons in layer 5. RMacL3-01 elicited functional levels of channelrhodopsin expression that enabled optical activation of single- and multi-unit activity in NHP DLFPC. Together, these results and resources establish a solid foundation to study cell type specific principles of primate cognitive functions.

neuroscience↗

bioRxiv2024

Developmental changes in mouse motor skill learning and cortical circuitry

Learning motor skills requires plasticity in the primary motor cortex (M1). But the capacity for cortical circuit plasticity varies over developmental age in sensory cortex. This study assesses the normal developmental trajectory of motor learning to assess how aptitude might vary with age. We trained mice of both sexes to run on a custom accelerating rotarod at ages from postnatal day (P) 20 to P120, tracking paw position and quantifying time to fall and changes in gait pattern. While animals of all ages were able to perform better after five training sessions, performance improved most rapidly on the first training day for mice between ages P30-60, suggesting an age with heightened plasticity. Learning this task required M1, because pharmacological inactivation of M1 prevented improvement in task performance. Paw position and gait patterns changed with learning, though differently between age groups. Successful mice learned to shift their gait from hopping to walking. Notably, this shift in gait happened earlier in the trial for forelimbs in comparison to hindlimbs. Thus, motor plasticity might more readily occur in forelimbs. Changes in gait and other kinematic parameters are an additional learning metric beyond time to fall, offering insight into how mice improve performance. Overall, these results suggest mouse motor learning has a developmental trajectory. SignificancePlasticity in sensory cortex is restricted to a limited developmental window. Learning motor skills requires motor cortex plasticity, but it is unknown whether learning aptitude changes over development. Here, we define the developmental trajectory of motor learning aptitude for the accelerating rotarod task in mice, demonstrating a sensitive period for motor learning. Learning peaks at P30-P60, with mice learning to shift from hopping to walking gait to stay on the rotarod longer. Learning this task depends on M1. Further, the gait shift in forelimbs precedes hindlimbs. Knowing the peak in motor plasticity identifies the time window at which we should seek to understand the circuit basis of motor learning plasticity in cortex.

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bioRxiv2024

Dopamine mediated plasticity preserves excitatory connections to direct pathway striatal projection neurons and motor function in a mouse model of Parkinson's disease

The cardinal symptoms of Parkinsons disease (PD) such as bradykinesia and akinesia are debilitating, and treatment options remain inadequate. The loss of nigrostriatal dopamine neurons in PD produces motor symptoms by shifting the balance of striatal output from the direct (go) to indirect (no-go) pathway in large part through changes in the excitatory connections and intrinsic excitabilities of the striatal projection neurons (SPNs). Here, we report using two different experimental models that a transient increase in striatal dopamine and enhanced D1 receptor activation, during 6-OHDA dopamine depletion, prevent the loss of mature spines and dendritic arbors on direct pathway projection neurons (dSPNs) and normal motor behavior for up to 5 months. The primary motor cortex and midline thalamic nuclei provide the major excitatory connections to SPNs. Using ChR2-assisted circuit mapping to measure inputs from motor cortex M1 to dorsolateral dSPNs, we observed a dramatic reduction in both experimental model mice and controls following dopamine depletion. Changes in the intrinsic excitabilities of SPNs were also similar to controls following dopamine depletion. Future work will examine thalamic connections to dSPNs. The findings reported here reveal previously unappreciated plasticity mechanisms within the basal ganglia that can be leveraged to treat the motor symptoms of PD.

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bioRxiv2023

Symmetry in frontal but not motor and somatosensory corticocortical and corticostriatal circuitry

Neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision making, where lateralization of function may be less important. This study contrasted the topographic precision of cell type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes. While sensory cortical areas had strongly topographic outputs to ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. Motor cortex had somewhat stronger projections, but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision making. Significance StatementEach cerebral hemisphere is responsible for sensation and movement of the opposite side of the body. Many axonal projections cross the midline to target contralateral areas. Crossed corticocortical, corticostriatal, and corticothalamic projections originate from much of neocortex, but how these projections vary across cortical regions and cell types is unknown. We quantify differences in the strength and targeting of ipsilateral and contralateral projections from frontal, motor, and somatosensory areas. The contralateral corticocortical and corticostriatal projections are proposed to play a larger role in frontal areas than in sensory or motor ones as a circuit basis for unifying computation across hemispheres in motor planning, while contralateral connectivity plays a smaller role in sensory and motor processing.

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bioRxiv2022

Long-range inhibitory neurons mediate cortical neurovascular coupling

Neuronal activity evokes a vascular response that is essential to sustain brain function. We show that neurovascular coupling (NVC) is mediated by long-range projecting GABAergic neurons that express Tacr1. Whisker stimulation elicited Tacr1 neuron activity in the barrel cortex through feed-forward excitatory pathways. Optogenetic activation of Tacr1 neurons elicited vasodilation, whereas inhibition significantly reduced whisker-evoked hemodynamic responses. Moreover, vasodilation was preceded by capillary pericyte activity, demonstrating a mechanism for NVC.

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bioRxiv2022

Correlated somatosensory input in parvalbumin/pyramidal cells in mouse motor cortex

In mammalian cortex, feedforward excitatory connections recruit feedforward inhibition. This is often carried by parvalbumin (PV+) interneurons, which may densely connect to local pyramidal (Pyr) neurons. Whether this inhibition affects all local excitatory cells indiscriminately or is targeted to specific subnetworks is unknown. Here, we test how feedforward inhibition is recruited by using 2-channel circuit mapping to excite cortical and thalamic inputs to PV+ interneurons and Pyr neurons in female and male mouse motor cortex. Single Pyr and PV+ neurons receive input from both cortex and thalamus. Connected pairs of PV+ interneurons and excitatory Pyr neurons receive correlated cortical and thalamic inputs. While PV+ interneurons are more likely to form local connections to Pyr neurons, Pyr neurons are much more likely to form reciprocal connections with PV+ interneurons that inhibit them. This suggests that Pyr neurons are embedded in local subnetworks. Excitatory inputs to M1 can thus target inhibitory networks in a specific pattern which permits recruitment of feedforward inhibition to specific subnetworks within the cortical column. SIGNIFICANCE STATEMENTIncoming sensory information to motor cortex (M1) excites neurons to plan and control movements. This input also recruits feedforward inhibition. Whether inhibition indiscriminately suppresses cortical excitation or forms specific subnetworks is unclear. Specific differences in connectivity in circuits promoting different movements might assist in motor control. We show that input to connected pairs of pyramidal (Pyr) excitatory neurons and parvalbumin (PV+) inhibitory interneurons is more strongly correlated than non-connected pairs, suggesting the integration of interneurons into specific cortical subnetworks. Despite sparse connections between these cells, pyramidal neurons are vastly more likely (3x) to excite PV+ cells connected to them. Thus, inhibition integrates into specific circuits in motor cortex, suggesting that separate, specific circuits exist for recruitment of feedforward inhibition.

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bioRxiv2021

Organization of cortical and thalamic input to inhibitory neurons in mouse motor cortex

Intracortical inhibition in motor cortex (M1) regulates movement and motor learning. If inhibitory cell types and cortical laminae targeted by cortical and thalamic afferents differ, then these afferents play different roles in regulating M1 output. We quantified input to two classes of M1 interneurons, parvalbumin+ (PV) fast-spiking cells and somatostatin+ (SOM) low-threshold-spiking cells, using monosynaptic rabies tracing. We then compared anatomical connectivity and functional connectivity based on synaptic strength from sensory cortex and thalamus. Functionally, each input innervated M1 interneurons with a unique laminar profile. Different interneuron types were excited in a distinct, complementary manner, suggesting feedforward inhibition proceeds selectively via distinct circuits. Specifically, somatosensory cortex (S1) inputs primarily targeted PV+ neurons in upper layers (L2/3) but SOM+ neurons in middle layers (L5). Somatosensory thalamus (PO) inputs targeted PV+ neurons in middle layers (L5). In contrast to sensory cortical areas, thalamic input to SOM+ neurons was equivalent to PV+ neurons. Thus, long-range excitatory inputs target inhibitory neurons in an area and cell type-specific manner which contrasts with input to neighboring pyramidal cells. In contrast to feedforward inhibition providing generic inhibitory tone in cortex, circuits are selectively organized to recruit inhibition matched to incoming excitatory circuits.

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bioRxiv2018

Cell type-specific variation of somatotopic precision across corticostriatal projections

The striatum shows general topographic organization and regional differences in behavioral functions. How corticostriatal topography differs across cortical areas and cell types to support these distinct functions is unclear. This study contrasted corticostriatal projections from two layer 5 cell types, intratelencephalic (IT-type) and pyramidal tract (PT-type) neurons, using viral vectors expressing fluorescent reporters in Cre-driver mice. Long-range corticostriatal projections from sensory and motor cortex are somatotopic, with a decreasing somatotopic specificity as injections move from sensory to motor and frontal areas. Somatotopic organization differs between IT-type and PT-type neurons, including injections in the same site, with IT-type neurons having higher somatotopic stereotypy than PT-type neurons. Furthermore, IT-type projections from interconnected cortical areas have stronger correlations in corticostriatal targeting than PT-type projections do. Thus, as predicted by a long-standing basal ganglia model, corticostriatal projections of interconnected cortical areas form parallel circuits in basal ganglia-thalamus-cortex loops.

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bioRxiv2017

The Transcriptional Logic of Mammalian Neuronal Diversity

The mammalian nervous system is constructed of many cell types, but the principles underlying this diversity are poorly understood. To assess brain-wide transcriptional diversity, we sequenced the transcriptomes of the largest collection of genetically and anatomically identified neuronal classes. Using improved expression metrics that distinguish information content from signal-to-noise-ratio, we found that homeobox transcription factors contain the highest information about cell types and have the lowest noise. Genes that contribute the most to neuronal diversity tend to be long and enriched in factors specifically involved in neuronal function. Genome accessibility measurements reveal that long genes have more candidate regulatory elements arrayed in more distinct patterns. These elements frequently overlap interspersed repeats (mobile elements) and the pattern of repeats is predictive of gene expression. New regulatory sites resulting from elongation of neuronal genes by mobile elements may be an evolutionary force enhancing nervous system complexity.

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