The ventral pallidum (VP) is an integral locus in the reward circuitry and a major target of GABAergic innervation of both D1-medium spiny neurons (MSNs) and D2-MSNs from the nucleus accumbens. The VP contains populations of GABAergic [VPGABA, GAD2(+), or VGluT(–)] and glutamatergic [VPGlutamate, GAD2(–), or VGluT(+)] cells that facilitate positive reinforcement and behavioral avoidance, respectively. MSN efferents to the VP exert opponent control over behavioral reinforcement with activation of D1-MSN afferents promoting and D2-MSN afferents inhibiting reward seeking. How this afferent-specific and cell type-specific control of reward seeking is integrated remains largely unknown. In addition to GABA, D1-MSNs corelease substance P to stimulate neurokinin 1 receptors (NK1Rs) and D2-MSNs corelease enkephalin to activate μ-opioid receptors (MORs) and δ-opioid receptors. These neuropeptides act in the VP to alter appetitive behavior and reward seeking. Using a combination of optogenetics and patch-clamp elect...

Highlighted Research Paper: [[L. J. Sukman and E. Stark, “Cortical pyramidal and parvalbumin cells exhibit distinct spatiotemporal extracellular electric potentials.” eNeuro (2022).][2]][2] []: /lookup/doi/10.1523/ENEURO.0265-22.2022

Here we describe the generation and characterization of a Cre knock-in mouse line that harbors a Cre insertion in the 3′UTR of the κ opioid receptor gene ( Oprk1 ) locus and provides genetic access to populations of κ opioid receptor (KOR)-expressing neurons throughout the brain. Using a combination of techniques including RNA in situ hybridization and immunohistochemistry, we report that Cre is expressed with high fidelity in KOR-expressing cells throughout the brain in this mouse line. We also provide evidence that Cre insertion does not alter basal KOR function. Baseline anxiety-like behaviors and nociceptive thresholds are unaltered in Oprk1-Cre mice. Chemogenetic activation of KOR-expressing cells in the basolateral amygdala (BLAKOR cells) resulted in several sex-specific effects on anxiety-like and aversive behaviors. Activation led to decreased anxiety-like behavior on the elevated plus maze and increased sociability in female but not in male Oprk1-Cre mice. Activation of BLAKOR cells also attenuate...

Neuroplasticity is maximal during development and declines in adulthood, especially for sensory cortices. On the other hand, the motor and prefrontal cortices retain plasticity throughout the lifespan. This difference has led to a modular view of plasticity in which different brain regions have their own plasticity mechanisms that do not depend or translate on others. Recent evidence shows that visual and motor plasticity share common neural mechanisms (e.g. GABAergic inhibition), indicating a possible link between these different forms of plasticity, however, the interaction between visual and motor plasticity has never been tested directly. Here we show that when visual and motor plasticity are elicited at the same time in adult humans, visual plasticity is impaired, while motor plasticity is spared. Moreover, simultaneous activation of working memory and visual plasticity also leads to impairment in visual plasticity. These unilateral interactions between visual, working memory and motor plasticity demo...

The balance between the degeneration and regeneration of damaged neurons depends on intrinsic and environmental variables. In nematodes, neuronal degeneration can be reversed by intestinal GABA and lactate-producing bacteria, or by hibernation driven by food deprivation. However, it is not known whether these neuroprotective interventions share common pathways to drive regenerative outcomes. Using a well-established neuronal degeneration model in the touch circuit of the bacterivore nematode Caenorhabditis elegans, we investigate the mechanistic commonalities between neuroprotection offered by the gut microbiota and hunger-induced diapause. Using transcriptomics approaches coupled to reverse genetics, we identify genes that are necessary for neuroprotection conferred by the microbiota. Some of these genes establish links between the microbiota and calcium homeostasis, diapause entry, and neuronal function and development. We find that extracellular calcium as well as mitochondrial MCU-1 and reticular SCA-1...

Neural population dynamics provide a key computational framework for understanding information processing in the sensory, cognitive, and motor functions of the brain. They systematically depict complex neural population activity, dominated by strong temporal dynamics as trajectory geometry in a low-dimensional neural space. However, neural population dynamics are poorly related to the conventional analytical framework of single-neuron activity, the rate-coding regime that analyzes firing-rate modulations using task parameters. To link the rate-coding and dynamical models, we developed a variant of state-space analysis in the regression subspace, which describes the temporal structures of neural modulations using continuous and categorical task parameters. In macaque monkeys, using two neural population datasets containing either of two standard task parameters, contiguous and categorical, we revealed that neural modulation structures are reliably captured by these task parameters in the regression subspace...

Network plasticity in the medial perforant path (MPP) of adult (5-9 mo) and aged (18-20 mo) urethane-anesthetized male and female Sprague-Dawley rats was characterized. Paired pulses probed recurrent networks before and after a moderate tetanic protocol. Adult females exhibited greater EPSP-spike coupling suggesting greater intrinsic excitability than adult males. Aged rats did not differ in EPSP-spike coupling but aged females had larger spikes at high currents than males. Paired pulses suggested lower GABA-B inhibition in females. Absolute population spike measures were larger post-tetani in female rats than male rats. Relative population spike increases were greatest in adult males relative to females and to aged males. EPSP slope potentiation was detected with normalization in some post-tetanic intervals for all groups except aged males. Tetani shortened spike latency across groups. Tetani-associated NMDA-mediated burst depolarizations were larger for the first two trains in each tetanus in adult males...

Here we describe the generation and characterization of a Cre knockin mouse line which harbors a Cre insertion in the 3’UTR of the kappa opioid receptor gene (Oprk1) locus and provides genetic access to populations of kappa opioid receptor (KOR)-expressing neurons throughout the brain. Using a combination of techniques including RNA in situ hybridization and immunohistochemistry, we report that Cre is expressed with high fidelity in KOR-expressing cells throughout the brain in this mouse line. We also provide evidence that Cre insertion does not alter basal KOR function. Baseline anxiety-like behaviors and nociceptive thresholds are unaltered in Oprk1-Cre mice. Chemogenetic activation of KOR-expressing cells in the basolateral amygdala (BLAKOR cells) resulted in several sex-specific effects on anxiety-like and aversive behaviors. Activation led to decreased anxiety-like behavior on the elevated plus maze and increased sociability in female but not in male Oprk1-Cre mice. Activation of BLAKOR cells also att...

Gamma-band oscillations (GBOs) are generated by fast-spiking interneurons and are critical for cognitive functions. Abnormalities in GBOs are frequently observed in schizophrenia and bipolar disorder and are strongly correlated with cognitive impairment. However, the underlying mechanisms are poorly understood. Studying GBOs in ex vivo preparations is challenging due to high energy demands and the need for continuous oxygen delivery to the tissue. As a result, GBOs are typically studied in brain tissue from very young animals or in experimental setups that maximize oxygen supply but compromise spatial resolution. Thus, there is a limited understanding of how GBOs interact within and between different brain structures remains or in brain tissue from mature animals. To address these limitations, we have developed a novel approach for studying GBOs in ex vivo hippocampal slices from mature animals, utilizing 60-channel, perforated microelectrode arrays (pMEAs). pMEAs enhance oxygen delivery and increase spati...

Ketamine, an NMDA antagonist, is widely used in clinical settings, particularly for its promising role as a rapid antidepressant. Recently, low-dose ketamine has gained attention due to its potential therapeutic benefits. However, the effects of low-dose ketamine on brain function, particularly higher cognitive functions of primate brains, are not fully understood. In this study, we used two macaque monkeys as subjects and found that acute low-dose ketamine administration significantly impairs the ability for arbitrary visuomotor mapping, a form of associative learning essential for flexible behaviors, including executions of learned stimuli-response contingency or learning of new contingencies. We conducted in-depth analyses and identified intrinsic characteristics of these ketamine-induced functional deficits, including lowered accuracy, prolonged time for planning and movement execution, increased tendency to make errors when visual cues are changed from trial to trial, and stronger impact on the associ...