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 two-channel circuit mapping to excite cortical and thalamic inputs to PV+ interneurons and Pyr neurons to mouse primary vibrissal motor cortex (M1). 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 and PV ensembles may be organized based on their local and long-range connections, a...

PyMouseTracks (PMT) is a scalable and customizable computer vision and radio frequency identification (RFID)-based system for multiple rodent tracking and behavior assessment that can be set up within minutes in any user-defined arena at minimal cost. PMT is composed of the online Raspberry Pi (RPi)-based video and RFID acquisition with subsequent offline analysis tools. The system is capable of tracking up to six mice in experiments ranging from minutes to days. PMT maintained a minimum of 88% detections tracked with an overall accuracy >85% when compared with manual validation of videos containing one to four mice in a modified home-cage. As expected, chronic recording in home-cage revealed diurnal activity patterns. In open-field, it was observed that novel noncagemate mouse pairs exhibit more similarity in travel trajectory patterns than cagemate pairs over a 10-min period. Therefore, shared features within travel trajectories between animals may be a measure of sociability that has not been previously...

Brain-derived neurotrophic factor (BDNF) is released from axon terminals originating in the cerebral cortex onto striatal neurons. Here, we characterized BDNF neurons in the corticostriatal circuitry. First, we used BDNF -Cre and Ribotag transgenic mouse lines to label BDNF-positive neurons in the cortex and detected BDNF expression in all the subregions of the prefrontal cortex (PFC). Next, we used a retrograde viral tracing strategy, in combination with BDNF -Cre knock-in mice, to map the cortical outputs of BDNF neurons in the dorsomedial and dorsolateral striatum (DMS and DLS, respectively). We found that BDNF- expressing neurons located in the medial prefrontal cortex (mPFC) project mainly to the DMS, and those located in the primary and secondary motor cortices (M1 and M2, respectively) and agranular insular cortex (AI) project mainly to the DLS. In contrast, BDNF- expressing orbitofrontal cortical (OFC) neurons differentially target the dorsal striatum (DS) depending on their mediolateral and rostro...

Encoding and processing sensory information is key to understanding the environment and to guiding behavior accordingly. Characterizing the behavioral and neural correlates of these processes requires the experimenter to have a high degree of control over stimuli presentation. For auditory stimulation in animals with relatively large heads, this can be accomplished by using headphones. However, it has proven more challenging in smaller species, such as rats and mice, and has been only partially solved using closed-field speakers in anesthetized or head-restrained preparations. To overcome the limitations of such preparations and to deliver sound with high precision to freely moving animals, we have developed a set of miniature headphones for rats. The headphones consist of a small, skull-implantable base attached with magnets to a fully adjustable structure that holds the speakers and keeps them in the same position with respect to the ears.

Glaucoma is a neurodegenerative condition in which increased intraocular pressure (IOP) causes progressive degeneration of retinal ganglion cells (RGCs), the neurons projecting from the retina to secondary visual areas of the brain. Raised IOP results in apoptosis of RGCs because of damage to RGC axons at the optic nerve head. Axonal damage triggers disruption of RGC mitochondria, metabolism, and active transport. It also disturbs the anatomic distribution of excitatory connections in RGC targets, including the superior colliculus and the thalamic dorsal lateral geniculate nucleus (dLGN). However, the timeline of the processes linking initial damage to RGC death is not well characterized. It is especially unclear at which point functional changes begin in excitatory synapses between RGCs and target structures like the thalamocortical (TC) neurons in the dLGN. To solve this conundrum, Smith et al. (2022) established a timeline for the pathologic processes induced by raised IOP by studying the RGC to TC syna...

Tau is a microtubule-associated protein (MAP) that has multiple isoforms generated by alternative splicing of the MAPT gene at a range of 45–60 kDa [low-molecular-weight (LMW) tau] as well as a unique isoform termed Big tau containing an additional exon 4a encoding a large projecting domain of ∼250 aa to form a protein of 110 kDa. Big tau is expressed in adult PNS neurons such as DRG neurons and specific regions of CNS such as the cerebellum in a developmental transition from LMW tau to Big tau during the postnatal period. Despite a conserved size of the 4a exons across the vertebrate phylogeny, there is no sequence homology among different species outside the Mammalia class, which underscores the focus on structural preservation of Big tau. Despite the original discovery of Big tau in the early 1990s, there has been little progress elucidating its physiological properties and pathologic implications. We propose that Big tau may be able to improve axonal transport in projecting axons and speculate on the p...

Arousal powerfully influences cortical activity, in part by modulating local inhibitory circuits. Somatostatin (SOM)-expressing inhibitory interneurons are particularly well situated to shape local population activity in response to shifts in arousal, yet the relationship between arousal state and SOM activity has not been characterized outside of sensory cortex. To determine whether SOM activity is similarly modulated by behavioral state across different levels of the cortical processing hierarchy, we compared the behavioral modulation of SOM-expressing neurons in auditory cortex (AC), a primary sensory region, and posterior parietal cortex (PPC), an association-level region of cortex, in mice. Behavioral state modulated activity differently in AC and PPC. In PPC, transitions to high arousal were accompanied by large increases in activity across the full PPC neural population, especially in SOM neurons. In AC, arousal transitions led to more subtle changes in overall activity, as individual SOM and Non-SO...

A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here, we used Rab10+/− mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/− mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared with their Rab10+/+ littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs), including Stx2, Stx1b, Vegfa, and Lrrc25 (downregulated) and Prkaa2, Syt4, and Grin2d (upregulated). Behavioral testing showed that Rab10+/− mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink classical ...

Spinal cord stimulation (SCS) evokes fast epidural evoked compound action potential (ECAP) that represent activity of dorsal column axons, but not necessarily a spinal circuit response. Using a multimodal approach, we identified and characterized a delayed and slower potential evoked by SCS that reflects synaptic activity within the spinal cord. Anesthetized female Sprague Dawley rats were implanted with an epidural SCS lead, epidural motor cortex stimulation electrodes, an epidural spinal cord recording lead, an intraspinal penetrating recording electrode array, and intramuscular electromyography (EMG) electrodes in the hindlimb and trunk. We stimulated the motor cortex or the epidural spinal cord and recorded epidural, intraspinal, and EMG responses. SCS pulses produced characteristic propagating ECAPs (composed of P1, N1, and P2 waves with latencies <2 ms) and an additional wave (“S1”) starting after the N2. We verified the S1-wave was not a stimulation artifact and was not a reflection of hindlimb/trun...

Although casual drinkers are a majority of the alcohol drinking population, understanding of the long-term effects of chronic exposure to lower levels of alcohol is limited. Chronic exposure to lower doses of ethanol may facilitate the development of alcohol use disorders, potentially because of ethanol effects on reward learning and motivation. Indeed, our previously published findings showed that chronic low-dose ethanol exposure enhanced motivation for sucrose in male, but not female, mice. As the ventral hippocampus (vHPC) is sensitive to disruption by higher doses of chronic ethanol and tracks reward-related information, we hypothesized that this region is impacted by low-dose ethanol and, further, that manipulating vHPC activity would alter reward motivation. In vivo electrophysiological recordings of vHPC population neural activity during progressive ratio testing revealed that vHPC activity was suppressed in the period immediately after reward seeking (lever press) in ethanol-naive controls, wherea...