We have previously established that PV+ neurons and Npas1+ neurons are distinct neuron classes in the external globus pallidus (GPe): they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2+ neurons, which are a unique subclass within the Npas1+ class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes. By using these novel driver lines, we have provided the most exhaustive investigation of electrophysiological studies of GPe neuron subtypes to date. Corroborating our prior studies, GPe neurons can be divided into two statistically distinct clusters that map onto PV+ and Npas1+ classes. By combining optogenetics and machine learning-based tracking, we showed that optogenetic perturbation of GPe neuron subtypes generated unique behavioral structures. Our findings further highl...

Bats provide a powerful mammalian model to explore the neural representation of complex sounds, as they rely on hearing to survive in their environment. The inferior colliculus (IC) is a central hub of the auditory system that receives converging projections from the ascending pathway and descending inputs from auditory cortex. In this work, we build an artificial neural network to replicate auditory characteristics in IC neurons of the big brown bat. We first test the hypothesis that spectro-temporal tuning of IC neurons is optimized to represent the natural statistics of conspecific vocalizations. We estimate spectro-temporal receptive fields (STRF) of IC neurons and compare tuning characteristics to statistics of bat calls. The results indicate that the FM tuning of IC neurons is matched with the statistics. Then, we investigate this hypothesis on the network optimized to represent natural sound statistics and to compare its output with biological responses. We also estimate biomimetic STRF's from the a...

The isocortex of all mammals studied to date shows a progressive increase in the amount and continuity of background activity during early development. In humans the transition from a discontinuous (mostly silent, intermittently bursting) cortex to one that is continuously active is complete soon after birth and is a critical prognostic indicator. In the visual cortex of rodents this switch from discontinuous to continuous background activity occurs during the two days before eye-opening, driven by activity changes in relay thalamus. The factors that regulate the timing of continuity development, which enables mature visual processing, are unknown. Here we test the role of the retina, the primary input, in the development of continuous spontaneous activity in the visual cortex of mice using depth electrode recordings from Enucleated mice in vivo . Bilateral enucleation at postnatal day (P)6, one week prior to the onset of continuous activity, acutely silences cortex, yet firing rates and early oscillations...

Hypertension susceptibility in women increases at the transition to menopause, termed perimenopause, a state characterized by erratic estrogen fluctuation and extended hormone cycles. Elucidating the role of estrogen signaling in the emergence of hypertension during perimenopause has been hindered by animal models that are confounded by abrupt estrogen cessation or effects of aging. In the present study, accelerated ovarian failure (AOF) in estrogen receptor beta (ERβ) reporter mice was induced by 4-vinylcyclohexene diepoxide (VCD) in young mice to model early-stage ovarian failure (peri-AOF) characteristic of peri-menopause. It was found that administering ERβ agonists suppressed elevated blood pressure in a model of neurogenic hypertension induced by angiotensin II (AngII) in peri-AOF, but not age-matched male mice. It was also found that ERβ agonist administration in peri-AOF females, but not males, suppressed the heightened NMDA receptor signaling and reactive oxygen production in ERβ neurons in the hy...

We examined the signaling route for fever during localized inflammation in male and female mice, elicited by casein injection into a preformed air pouch. The localized inflammation gave rise to high concentrations of PGE2 and cytokines in the air pouch, and elevated levels of these inflammatory mediators in plasma. There were also elevated levels of PGE2 in the cerebrospinal fluid, although there was little evidence for PGE2 synthesis in the brain. Global deletion of the PGE2 EP3 receptor abolished the febrile response as did deletion of the EP3 receptor in neural cells, whereas its deletion on peripheral nerves had no effect, implying that PGE2 action on this receptor in the CNS elicited the fever. Global deletion of the interleukin-1 receptor type 1 (IL-1R1) also abolished the febrile response, whereas its deletion on neural cells or peripheral nerves had no effect. However, deletion of the IL-1R1 on brain endothelial cells, as well as deletion of the interleukin-6 receptor α on these cells, attenuated t...

The ability of mammalian taste cells to respond to fatty acids (FAs) has garnered significant attention of late and has been proposed to represent a sixth primary taste. With few exceptions, studies on FA taste have centered exclusively on polyunsaturated FAs, most notably on linoleic acid. In the current study, we have identified an additional FA receptor, GPR84, in the gustatory system that responds to the medium chains saturated FAs (MCFAs) in male mice. GPR84 ligands activate both Type II and Type III taste cells in calcium imaging and patch clamp recording assays. MCFAs depolarize and lead to a rise in intracellular free [Ca2+] in mouse taste cells in a concentration-dependent fashion and the relative ligand specificity in taste cells is consistent with the response profile of GPR84 expressed in a heterologous system. A systemic Gpr84-/- mouse model reveals a specific deficit in both the neural (via chorda tympani recording) and behavioral responses to administration of oral MCFAs compared to wild typ...

People with strabismus acquired during childhood do not experience diplopia (double vision). To investigate how perception of the duplicate image is suppressed, we raised two male monkeys with alternating exotropia by disinserting the medial rectus muscle in each eye at age 4 weeks. Once the animals were mature, they were brought to the laboratory and trained to fixate a small spot while recordings were made in V1. Drifting gratings were presented to the receptive fields of 500 single neurons for 8 interleaved conditions: 1) right eye monocular, 2) left eye monocular, 3) right eye’s field, right eye fixating, 4) right eye’s field, left eye fixating, 5) left eye’s field, right eye fixating, 6) left eye’s field, left eye fixating, 7) both eyes’ fields, right eye fixating, 8) both eyes’ fields, left eye fixating. As expected, ocular dominance histograms showed a monocular bias compared with normal animals, but many cells could still be driven via both eyes. Overall, neuronal responses were not affected by swi...

About half the people infected with human immunodeficiency virus (HIV) have neurocognitive deficits that often include memory impairment and hippocampal deficits, which can be exacerbated by opioid abuse. To explore the effects of opioids and HIV on hippocampal CA1 pyramidal neuron structure and function, we induced HIV-1 transactivator of transcription (Tat) expression in transgenic mice for 14 d and co-administered time-release morphine or vehicle subcutaneous implants during the final 5 d (days 9–14) to establish steady-state morphine levels. Morphine was withheld from some ex vivo slices during recordings to begin to assess the initial pharmacokinetic consequences of opioid withdrawal. Tat expression reduced hippocampal CA1 pyramidal neuronal excitability at lower stimulating currents. Pyramidal cell firing rates were unaffected by continuous morphine exposure. Behaviorally, exposure to Tat or high dosages of morphine impaired spatial memory Exposure to Tat and steady-state levels of morphine appeared ...

Among all voltage-gated potassium (Kv) channels, Kv2 channels are the most widely expressed in the mammalian brain. However, studying Kv2 in neurons has been challenging because of a lack of high-selective blockers. Recently, a peptide toxin, guangxitoxin-1E (GxTX), has been identified as a specific inhibitor of Kv2, thus facilitating the study of Kv2 in neurons. The mammalian dorsal cochlear nucleus (DCN) integrates auditory and somatosensory information. In the DCN, cartwheel inhibitory interneurons receive excitatory synaptic inputs from parallel fibers conveying somatosensory information. The activation of parallel fibers drives action potentials in the cartwheel cells up to 130 Hz in vivo , and the excitation of cartwheel cells leads to the strong inhibition of principal cells. Therefore, cartwheel cells play crucial roles in monaural sound localization and cancelling detection of self-generated sounds. However, how Kv2 controls the high-frequency firing in cartwheel cells is unknown. In this study, w...

Adenosine acts as a neuromodulator and metabolic regulator of the brain through receptor dependent and independent mechanisms. In the brain, adenosine is tightly controlled through its metabolic enzyme adenosine kinase (ADK), which exists in a cytoplasmic (ADK-S) and nuclear (ADK-L) isoform. We recently discovered that ADK-L contributes to adult hippocampal neurogenesis regulation. Although the cerebellum (CB) is a highly plastic brain area with a delayed developmental trajectory, little is known about the role of ADK. Here, we investigated the developmental profile of ADK expression in C57BL/6 mice CB and assessed its role in developmental and proliferative processes. We found high levels of ADK-L during cerebellar development, which was maintained into adulthood. This pattern contrasts with that of the cerebrum, in which ADK-L expression is gradually downregulated postnatally and largely restricted to astrocytes in adulthood. Supporting a functional role in cell proliferation, we found that the ADK inhib...