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Perception can be refined by experience, up to certain limits. It is unclear whether perceptual limits are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest that peripheral nerve stimulation, specifically vagus nerve stimulation (VNS), can alter neural activity and augment experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS applied during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Two-photon imaging revealed VNS induced changes to auditory cortical responses and activated cortically projecting cholinergic axons. Anatomical and optogenetic experiments indicated that VNS can enhance task performance through activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS and may contribute to further refinement of VNS methodology for clinical conditions. Perceptual abilities can be improved by training, up to certain limits. Martin et al. show that vagus nerve stimulation in mice boosts performance on an auditory task via cholinergic modulation, beyond the level achieved by training alone.

Involved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells. We show that , which codes for the Kir6.1 subunit of a certain type of ATP-sensitive potassium (K ) channel, is highly expressed in murine splenic and uterine NK cells compared to other K channels previously identified in NK cells. expression is highest in the most mature subset of splenic NK cells (CD27 /CD11b ) and in NKG2A or Ly49C/I educated uterine NK cells. Using patch clamping, we show that a subset of NK cells expresses a current sensitive to the Kir6.1 blocker PNU-37883A. does not participate in NK cell degranulation in response to tumor cells in vitro or rejection of tumor cells , or IFN-γ release. Transcriptomics show that genes previously implicated in NK cell development are amongst those differentially expressed in CD27 /CD11b NK cells deficient for . Indeed, we found that mice with NK-cell specific gene ablation have fewer CD27 /CD11b and KLRG-1 NK cells in the bone barrow and spleen. These results show that the K subunit Kir6.1 has a key role in NK-cell development.

Sexual and aggressive behaviors are fundamental to animal survival and reproduction. The medial preoptic nucleus (MPN) and ventrolateral part of the ventromedial hypothalamus (VMHvl) are essential regions for male sexual and aggressive behaviors, respectively. While key inhibitory inputs to the VMHvl and MPN have been identified, the extrahypothalamic excitatory inputs essential for social behaviors remain elusive. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the posterior amygdala (PA) as a main source of excitatory inputs to the hypothalamus and key mediators for mating and fighting in male mice. We find two largely distinct PA subpopulations that differ in connectivity, gene expression, in vivo responses and social behavior relevance. MPN-projecting PAEsr1+ cells are activated during mating and are necessary and sufficient for male sexual behaviors, while VMHvl-projecting PAEsr1+ cells are excited during intermale aggression and promote attacks. These findings place the PA as a key node in both male aggression and reproduction circuits.Yamaguchi et al. identify a little-known amygdalar region, the posterior amygdala, as a key node in male mouse social behaviors. Two largely non-overlapping subpopulations in the posterior amygdala form parallel projections to distinct hypothalamic regions to regulate mating and fighting.

Infant cries evoke powerful responses in parents 1 – 4 . Whether parental animals are intrinsically sensitive to neonatal vocalizations, or instead learn about vocal cues for parenting responses is unclear. In mice, pup-naive virgin females do not recognize the meaning of pup distress calls, but retrieve isolated pups to the nest after having been co-housed with a mother and litter 5 – 9 . Distress calls are variable, and require co-caring virgin mice to generalize across calls for reliable retrieval 10 , 11 . Here we show that the onset of maternal behaviour in mice results from interactions between intrinsic mechanisms and experience-dependent plasticity in the auditory cortex. In maternal females, calls with inter-syllable intervals (ISIs) from 75 to 375 milliseconds elicited pup retrieval, and cortical responses were generalized across these ISIs. By contrast, naive virgins were neuronally and behaviourally sensitized to the most common (‘prototypical’) ISIs. Inhibitory and excitatory neural responses were initially mismatched in the cortex of naive mice, with untuned inhibition and overly narrow excitation. During co-housing experiments, excitatory responses broadened to represent a wider range of ISIs, whereas inhibitory tuning sharpened to form a perceptual boundary. We presented synthetic calls during co-housing and observed that neurobehavioural responses adjusted to match these statistics, a process that required cortical activity and the hypothalamic oxytocin system. Neuroplastic mechanisms therefore build on an intrinsic sensitivity in the mouse auditory cortex, and enable rapid plasticity for reliable parenting behaviour. The onset of maternal behaviour in mice involves an interaction between intrinsic tuning of auditory cortical neurons and experience-dependent plasticity.

Striatal interneurons and projection neurons are differentially tuned to spectral components of synaptic input signals, and this is especially apparent in their responses to oscillations. The broad frequency tuning of spike responses in somatostatin/NPY-expressing low threshold spike (LTS) interneurons sets them apart from other GABAergic interneurons in the striatum as well as from the spiny projection (SP) neurons. The mechanism of LTS interneuron spiking resonance was unrelated to its membrane impedance resonance; abolition of membrane impedance resonance did not alter the spiking resonance. A comparison of the phase resetting curves (PRCs) and spiking resonance profiles of LTS interneurons and SP neurons revealed a relationship between the frequency sensitivity of the neurons and the spectral components of their infinitesimal PRCs. Sine wave input currents could control spike timing in SP neurons and LTS interneurons only to the extent that their PRCs contained Fourier modes of corresponding frequency. LTS interneurons’ PRCs contain larger high-frequency components, endowing the neurons with enhanced responses to input frequencies faster than the cells’ autonomous firing rates. This enables the LTS cells to be entrained by frequency components of the input signal to which SP neurons are less responsive. In addition to its effects on firing rate, striatal feedforward inhibition by LTS interneurons may regulate the entrainment of SP neurons by oscillatory afferents.

INTRODUCTION It is unclear how early neuronal deficits occur in tauopathies, if these are associated with changes in neuronal network activity, and if they can be alleviated with therapies. METHODS To address this, we performed in vivo two‐photon Ca2+ imaging in tauopathy mice at 6 versus 12 months, compared to controls, and treated the younger animals with a tau antibody. RESULTS Neuronal function was impaired at 6 months but did not deteriorate further at 12 months, presumably because cortical tau burden was comparable at these ages. At 6 months, neurons were mostly hypoactive, with enhanced neuronal synchrony, and had dysregulated responses to stimulus. Ex vivo, electrophysiology revealed altered synaptic transmission and enhanced excitability of motor cortical neurons, which likely explains the altered network activity. Acute tau antibody treatment reduced pathological tau and gliosis and partially restored neuronal function. DISCUSSION Tauopathies are associated with early neuronal deficits that can be attenuated with tau antibody therapy. Highlights Neuronal hypofunction in awake and behaving mice in early stages of tauopathy. Altered network activity disrupted local circuitry engagement in tauopathy mice. Enhanced neuronal excitability and altered synaptic transmission in tauopathy mice. Tau antibody acutely reduced soluble phospho‐tau and improved neuronal function.

Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3α,5α)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence. To systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)×DBA/2J (D2) (BXD) mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p<0.0001) with a heritability of ∼0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p<0.0001) with heritability of ∼0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels across BXD strains were further shown to be co-regulated with networks of genes linked to neuronal, immune, and endocrine function. DOC levels and its responses to dexamethasone were associated with several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories. Both basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. DOC levels were also strongly correlated with networks of genes associated with neuronal function, innate immune pathways, and steroid metabolism, likely linked to behavioral phenotypes.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The complete and correct funding information is: \"This study was supported by the National Institute of Health NIAAA grants INIA-UO1-AA013641 (PP), INIA-UO1-AA016672 and R37-AA010564 (ALM), INIA-UO1-AA016662 (MFM), INIA-UO1-AA014425 (LL-RWW), INIA-UO1-AA13499, INIA-UO1-AA13513 and AA017590 (RWW) and by the University Research Council of the University of North Carolina at Chapel Hill (PP). (2011) Correction: Genetic Analysis of the Neurosteroid Deoxycorticosterone and Its Relation to Alcohol Phenotypes: Identification of QTLs and Downstream Gene Regulation.