Neural circuitry for maternal oxytocin release induced by infant cries.

Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing1-6. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers7, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.

Tob Regulates the Timing of Sleep Onset at Night in Drosophila.

Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating the molecular components of the core circadian oscillator, the output mechanisms by which this robust oscillator generates rhythmic sleep behavior remain poorly understood. At the cellular level, growing evidence suggests that subcircuits in the master circadian pacemaker suprachiasmatic nucleus (SCN) in mammals and in the clock network in Drosophila regulate distinct aspects of sleep. Thus, to identify novel molecules regulating the circadian timing of sleep, we conducted a large-scale screen of mouse SCN-enriched genes in Drosophila Here, we show that Tob (Transducer of ERB-B2) regulates the timing of sleep onset at night in female fruit flies. Knockdown of Tob pan-neuronally, either constitutively or conditionally, advances sleep onset at night. We show that Tob is specifically required in "evening neurons" (the LNds and the fifth s-LNv) of the clock network for proper timing of sleep onset. Tob levels cycle in a clock-dependent manner in these neurons. Silencing of these "evening" clock neurons results in an advanced sleep onset at night, similar to that seen with Tob knockdown. Finally, sharp intracellular recordings demonstrate that the amplitude and kinetics of LNd postsynaptic potentials (PSPs) cycle between day and night, and this cycling is attenuated with Tob knockdown in these cells. Our data suggest that Tob acts as a clock output molecule in a subset of clock neurons to potentiate their activity in the evening and enable the proper timing of sleep onset at night.

Vagus nerve stimulation recruits the central cholinergic system to enhance perceptual learning.

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.

Cytoarchitecture, myeloarchitecture, and parcellation of the chimpanzee inferior parietal lobe.

The parietal lobe is a region of especially pronounced change in human brain evolution. Based on comparative neuroanatomical studies, the inferior parietal lobe (IPL) has been shown to be disproportionately larger in humans relative to chimpanzees and macaques. However, it remains unclear whether the underlying histological architecture of IPL cortical areas displays human-specific organization. Chimpanzees are among the closest living relatives of humans, making them an ideal comparative species to investigate potential evolutionary changes in the IPL. We parcellated the chimpanzee IPL using cytoarchitecture and myeloarchitecture, in combination with quantitative comparison of cellular features between the identified cortical areas. Four major areas on the lateral convexity of the chimpanzee IPL (PF, PFG, PG, OPT) and two opercular areas (PFOP, PGOP) were identified, similar to what has been observed in macaques. Analysis of the quantitative profiles of cytoarchitecture showed that cell profile density was significantly different in a combination of layers III, IV, and V between bordering cortical areas, and that the density profiles of these six areas supports their classification as distinct. The similarity to macaque IPL cytoarchitecture suggests that chimpanzees share homologous IPL areas. In comparison, human rostral IPL is reported to differ in its anatomical organization and to contain additional subdivisions, such as areas PFt and PFm. These changes in human brain evolution might have been important as tool making capacities became more complex.

A clock-dependent brake for rhythmic arousal in the dorsomedial hypothalamus.

Circadian clocks generate rhythms of arousal, but the underlying molecular and cellular mechanisms remain unclear. In Drosophila, the clock output molecule WIDE AWAKE (WAKE) labels rhythmic neural networks and cyclically regulates sleep and arousal. Here, we show, in a male mouse model, that mWAKE/ANKFN1 labels a subpopulation of dorsomedial hypothalamus (DMH) neurons involved in rhythmic arousal and acts in the DMH to reduce arousal at night. In vivo Ca2+ imaging reveals elevated DMHmWAKE activity during wakefulness and rapid eye movement (REM) sleep, while patch-clamp recordings show that DMHmWAKE neurons fire more frequently at night. Chemogenetic manipulations demonstrate that DMHmWAKE neurons are necessary and sufficient for arousal. Single-cell profiling coupled with optogenetic activation experiments suggest that GABAergic DMHmWAKE neurons promote arousal. Surprisingly, our data suggest that mWAKE acts as a clock-dependent brake on arousal during the night, when mice are normally active. mWAKE levels peak at night under clock control, and loss of mWAKE leads to hyperarousal and greater DMHmWAKE neuronal excitability specifically at night. These results suggest that the clock does not solely promote arousal during an animal's active period, but instead uses opposing processes to produce appropriate levels of arousal in a time-dependent manner.

Astroglial Calcium Signaling Encodes Sleep Need in Drosophila.

Sleep is under homeostatic control, whereby increasing wakefulness generates sleep need and triggers sleep drive. However, the molecular and cellular pathways by which sleep need is encoded are poorly understood. In addition, the mechanisms underlying both how and when sleep need is transformed to sleep drive are unknown. Here, using ex vivo and in vivo imaging, we show in Drosophila that astroglial Ca2+ signaling increases with sleep need. We demonstrate that this signaling is dependent on a specific L-type Ca2+ channel and is necessary for homeostatic sleep rebound. Thermogenetically increasing Ca2+ in astrocytes induces persistent sleep behavior, and we exploit this phenotype to conduct a genetic screen for genes required for the homeostatic regulation of sleep. From this large-scale screen, we identify TyrRII, a monoaminergic receptor required in astrocytes for sleep homeostasis. TyrRII levels rise following sleep deprivation in a Ca2+-dependent manner, promoting further increases in astrocytic Ca2+ and resulting in a positive-feedback loop. Moreover, our findings suggest that astrocytes then transmit this sleep need to a sleep drive circuit by upregulating and releasing the interleukin-1 analog Spätzle, which then acts on Toll receptors on R5 neurons. These findings define astroglial Ca2+ signaling mechanisms encoding sleep need and reveal dynamic properties of the sleep homeostatic control system.

Comparison of bonobo and chimpanzee brain microstructure reveals differences in socio-emotional circuits.

Despite being closely related, bonobos and chimpanzees exhibit several behavioral differences. For instance, studies indicate that chimpanzees are more aggressive, territorial, and risk-taking, while bonobos exhibit greater social tolerance and higher rates of socio-sexual interactions. To elucidate the potential neuroanatomical variation that accompanies these differences, we examined the microstructure of selected brain areas by quantifying the neuropil fraction, a measure of the relative tissue area occupied by structural elements of connectivity (e.g., dendrites, axons, and synapses) versus cell bodies. In bonobos and chimpanzees, we compared neuropil fractions in the nucleus accumbens (NAc; core and shell), amygdala (whole, accessory basal, basal, central and lateral nuclei), anterior cingulate cortex (ACC; dorsal and subgenual), anterior insular cortex (AIC), and primary motor cortex (M1). In the dorsal ACC and frontoinsular cortex (FI) we also quantified numbers of von Economo neurons (VENs), a unique subset of neurons thought to be involved in rapid information processing during social interactions. We predicted that the neuropil fraction and number of VENs in brain regions associated with socio-emotional processing would be higher in bonobos. In support of this hypothesis, we found that bonobos had significantly greater neuropil in the central and accessory basal nuclei of the amygdala, as well as layers V-VI of the subgenual ACC. However, we did not find a difference in the numbers of VENs between the two species. These findings support the conclusion that bonobo and chimpanzee brains differ in the anatomical organization of socio-emotional systems that may reflect species-specific variation in behavior.

Structure of the polyisoprenyl-phosphate glycosyltransferase GtrB and insights into the mechanism of catalysis.

The attachment of a sugar to a hydrophobic polyisoprenyl carrier is the first step for all extracellular glycosylation processes. The enzymes that perform these reactions, polyisoprenyl-glycosyltransferases (PI-GTs) include dolichol phosphate mannose synthase (DPMS), which generates the mannose donor for glycosylation in the endoplasmic reticulum. Here we report the 3.0 Å resolution crystal structure of GtrB, a glucose-specific PI-GT from Synechocystis, showing a tetramer in which each protomer contributes two helices to a membrane-spanning bundle. The active site is 15 Å from the membrane, raising the question of how water-soluble and membrane-embedded substrates are brought into apposition for catalysis. A conserved juxtamembrane domain harbours disease mutations, which compromised activity in GtrB in vitro and in human DPM1 tested in zebrafish. We hypothesize a role of this domain in shielding the polyisoprenyl-phosphate for transport to the active site. Our results reveal the basis of PI-GT function, and provide a potential molecular explanation for DPM1-related disease.