The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson's disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a...

Qiaoling Cui, Xixun Du, Isaac Y. M. Chang, Arin Pamukcu, Varoth Lilascharoen, et al. (see pages [3966–3987][1]) The dorsal striatum is involved in action selection and sequencing. Whereas the dorsomedial subdivision is thought to mediate goal-directed actions, the dorsolateral subdivision is

The serotonergic system is strongly implicated in anxiety and depression, and it is the first-line target for pharmacological treatment ([Tamblyn et al., 2019][1]). Genetic factors predispose people to these disorders, but the anatomic and molecular diversity of the main serotonergic nuclei, the

To thrive in dynamic environments, animals must be capable of rapidly and flexibly adapting behavioral responses to a changing context and internal state. Examples of behavioral flexibility include faster stimulus responses when attentive and slower responses when distracted. Contextual or state-dependent modulations may occur early in the cortical hierarchy and may be implemented via top-down projections from corticocortical or neuromodulatory pathways. However, the computational mechanisms mediating the effects of such projections are not known. Here, we introduce a theoretical framework to classify the effects of cell type-specific top-down perturbations on the information processing speed of cortical circuits. Our theory demonstrates that perturbation effects on stimulus processing can be predicted by intrinsic gain modulation, which controls the timescale of the circuit dynamics. Our theory leads to counterintuitive effects, such as improved performance with increased input variance. We tested the mod...

Zebrafish models are used increasingly to study the molecular pathogenesis of Parkinson's disease (PD), owing to the extensive array of techniques available for their experimental manipulation and analysis. The ascending dopaminergic projection from the posterior tuberculum (TPp; diencephalic populations DC2 and DC4) to the subpallium is considered the zebrafish correlate of the mammalian nigrostriatal projection, but little is known about the neurophysiology of zebrafish DC2/4 neurons. This is an important knowledge gap, because autonomous activity in mammalian substantia nigra (SNc) dopaminergic neurons contributes to their vulnerability in PD models. Using a new transgenic zebrafish line to label living dopaminergic neurons, and a novel brain slice preparation, we conducted whole-cell patch clamp recordings of DC2/4 neurons from adult zebrafish of both sexes. Zebrafish DC2/4 neurons share many physiological properties with mammalian dopaminergic neurons, including the cell-autonomous generation of actio...

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...