The perception of our surrounding environment is an amalgamation of stimuli detected by sensory neurons. In C. elegans olfaction is an essential behavior that determines various behavioral functions such as locomotion, feeding and development. Sensory olfactory cues also initiate downstream neuroendocrine signaling that controls ageing, learning, development and reproduction. Innate sensory preferences towards odors (food, pathogens) and reproductive pheromones are modulated by 11 pairs of amphid chemosensory neurons in the head region of C. elegans . Amongst these sensory neurons, the ASI neuron has neuroendocrine functions and secretes neuropeptides, insulin-like peptide (DAF-28) and the TGF-β protein, DAF-7. Its expression levels are modulated by the presence of food (increased levels) and population density (decreased levels). A recent study has shown that EXP-1, an excitatory GABA receptor regulates DAF-7/TGF-β levels and participates in DAF-7/TGF- β mediated behaviors such as aggregation and borderin...

The impairment of cold-evoked activation of brown adipose tissue (BAT) in rats fed a high fat diet (HFD) requires the activity of a vagal afferent to the medial nucleus of the solitary tract (mNTS). We determined the role of transient receptor potential vanilloid 1 (TRPV1) activation in the mNTS, and of a dynorphin input to the median preoptic nucleus (MnPO) in the impaired BAT thermogenic response to cold in HFD-fed rats. The levels of some linoleic acid metabolites, which can act as endogenous TRPV1 agonists, were elevated in the NTS of HFD rats compared to chow-fed rats. In HFD rats, nanoinjections of the TRPV1 antagonist, capsazepine in the NTS rescued the impaired BAT sympathetic nerve activity (BAT SNA) and thermogenic responses to cold. In contrast, in chow-fed rats, cold-evoked BAT SNA and BAT thermogenesis were not changed by nanoinjections of capsazepine into the NTS. Axon terminals of NTS neurons that project to the dorsal lateral parabrachial nucleus (LPBd) were closely apposed to LPBd neurons...

Drugs of abuse engage overlapping but distinct molecular and cellular mechanisms to enhance dopamine (DA) signaling in the mesocorticolimbic circuitry. DA neurons of the ventral tegmental area (VTA) are key substrates of drugs of abuse and have been implicated in addiction-related behaviors. Enhanced VTA DA neurotransmission evoked by drugs of abuse can engage inhibitory G protein-dependent feedback pathways, mediated by GABAB receptors (GABABRs) and D2 DA receptors (D2Rs). Chemogenetic inhibition of VTA DA neurons potently suppressed baseline motor activity, as well as the motor-stimulatory effect of cocaine and morphine, confirming the critical influence of VTA DA neurons and inhibitory G protein signaling in these neurons on this addiction-related behavior. To resolve the relative influence of GABABR- and D2R-dependent signaling pathways in VTA DA neurons on behavioral sensitivity to drugs of abuse, we developed a neuron-specific viral CRISPR/Cas9 approach to ablate D2R and GABABR in VTA DA neurons. Abl...

Feeding and breathing are two functions vital to the survival of all vertebrate species. Throughout the evolution, vertebrates living in different environments have evolved drastically different modes of feeding and breathing through utilizing diversified orofacial and pharyngeal (oropharyngeal) muscles. The oropharyngeal structures are controlled by hindbrain neural circuits. The developing hindbrain shares strikingly conserved organizations and gene expression patterns across vertebrates, thus begs the question of how a highly conserved hindbrain generates circuits subserving diverse feeding/breathing patterns. In this review, we summarize major modes of feeding and breathing and principles underlying their coordination in many vertebrate species. We provide a hypothesis for the existence of a common hindbrain circuit at the phylotypic embryonic stage controlling oropharyngeal movements that is shared across vertebrate species; and reconfiguration and repurposing of this conserved circuit give rise to mo...

The basal ganglia have long been considered crucial for associative learning, but whether they also are involved in another type of learning, error-based motor learning, is not clear. Error-based learning has been considered the province of the cerebellum. However, learning to use a robotic arm and saccade adaptation, which use error-based learning, are facilitated by motivation, which is a function of the basal ganglia. Additionally, patients with Parkinson’s disease, a basal ganglia deficit, show slower saccade adaptation than age matched controls. To further investigate whether the basal ganglia actually influence error-based learning, we reversibly inactivated the oculomotor portion of the substantia nigra pars reticulata in two monkeys and tested saccade adaptation. Here we show that nigral inactivation affected saccade adaptation. In particular, the inactivation facilitated the amplitude decrease adaptation of ipsiversive saccades. Consistent with previous studies, no effect was seen on the amplitude...

Seizures invite seizures. At the initial stage of epilepsy, seizures intensify with each episode; however, the mechanisms underlying this exacerbation remain to be solved. Astrocytes have a strong control over neuronal excitability and the mode of information processing. This control is accomplished by adjusting the levels of various ions in the extracellular space. The network of astrocytes connected via gap junctions allows a wider or more confined distribution of these ions depending on the open probability of the gap junctions. K+ clearance relies on the K+ uptake by astrocytes and the subsequent diffusion of K+ through the astrocyte network. When astrocytes become uncoupled, K+ clearance becomes hindered. Accumulation of extracellular K+ leads to hyperexcitability of neurons. Here, using acute hippocampal slices from mice, we uncovered that brief periods of epileptiform activity result in gap junction uncoupling. In slices that experienced short-term epileptiform activity, extracellular K+ transients ...

Parkinson's disease (PD) is the most common neurodegenerative movement disorder in humans. Despite intense investigations, effective therapies are not yet available to halt the progression of PD. Gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, is known to decrease the risk of coronary heart disease by increasing the level of high-density lipoprotein cholesterol and decreasing the level of low-density lipoprotein cholesterol. This study underlines the importance of gemfibrozil in protecting dopaminergic neurons in an animal model of PD. Oral administration of the human equivalent dose of gemfibrozil protected tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra pars compacta and TH fibers in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-insulted mice of both sexes. Accordingly, gemfibrozil also normalized striatal neurotransmitters and improved locomotor activities in MPTP-intoxicated mice. Gemfibrozil-mediated protection of the nigr...

NMDARs are ligand-gated ion channels that cause an influx of Na+ and Ca2+ into postsynaptic neurons. The resulting intracellular Ca2+ transient triggers synaptic plasticity. When prolonged, it may induce excitotoxicity, but it may also activate negative feedback to control the activity of NMDARs. Here, we report that a transient rise in intracellular Ca2+ (Ca2+ challenge) increases the sensitivity of NMDARs but not AMPARs/kainate receptors to the endogenous inhibitory neurosteroid 20-oxo-5β-pregnan-3α-yl 3-sulfate and to its synthetic analogs, such as 20-oxo-5β-pregnan-3α-yl 3-hemipimelate (PAhPim). In cultured hippocampal neurons, 30 μm PAhPim had virtually no effect on NMDAR responses; however, following the Ca2+ challenge, it inhibited the responses by 62%; similarly, the Ca2+ challenge induced a 3.7-fold decrease in the steroid IC50 on recombinant GluN1/GluN2B receptors. The increase in the NMDAR sensitivity to PAhPim was dependent on three cysteines (C849, C854, and C871) located in the carboxy-termin...

The default mode network (DMN) is often associated with representing semantic, social, and situational content of contexts and episodes. The DMN may therefore be important for contextual decision-making, through representing situational constraints and simulating common courses of events. Most decision-making paradigms, however, use symbolic stimuli and instead implicate cognitive control regions, such as the multiple demand (MD) system. This fMRI study aimed to contrast the brain mechanisms underlying decision-making based on rich naturalistic contexts or symbolic cues. While performing an ongoing task, 40 human participants (25 female) responded to different sounds. For one sound, the stimulus-response mapping was fixed; responses for the other sounds depended on the visual context: either lifelike scenes or letter symbols, varying across participants. Despite minimal behavioral differences between the groups, posterior DMN regions showed increased activity during context-dependent decision-making using ...

In the neurobiology of syntax, a methodological challenge is to vary syntax while holding semantics constant. Changes in syntactic structure usually correlate with changes in meaning. We approached this challenge from a new angle. We deployed word lists—typically, the unstructured control in studies of syntax—as both test and control stimuli. Three-noun lists (“lamps, dolls, guitars”) were embedded in sentences (“The eccentric man hoarded lamps, dolls, guitars…”) and in longer lists (“forks, pen, toilet, rodeo, lamps, dolls, guitars…”). This allowed us to minimize contributions from lexical semantics and local phrasal combinatorics: the same words occurred in both conditions, and in neither case did the list items locally compose into phrases (e.g., “lamps” and “dolls” do not form a phrase). Crucially, the list partakes in a syntactic tree in one case but not the other. Lists-in-sentences increased source-localized MEG activity at ∼250–300 ms from each of the list item onsets in the left inferior frontal c...