Developing forebrain synapses are uniquely vulnerable to sleep loss.

Sleep is an essential behavior that supports lifelong brain health and cognition. Neuronal synapses are a major target for restorative sleep function and a locus of dysfunction in response to sleep deprivation (SD). Synapse density is highly dynamic during development, becoming stabilized with maturation to adulthood, suggesting sleep exerts distinct synaptic functions between development and adulthood. Importantly, problems with sleep are common in neurodevelopmental disorders including autism spectrum disorder (ASD). Moreover, early life sleep disruption in animal models causes long lasting changes in adult behavior. Different plasticity engaged during sleep necessarily implies that developing and adult synapses will show differential vulnerability to SD. To investigate distinct sleep functions and mechanisms of vulnerability to SD across development, we systematically examined the behavioral and molecular responses to acute SD between juvenile (P21-28), adolescent (P42-49) and adult (P70-100) mice of both sexes. Compared to adults, juveniles lack robust adaptations to SD, precipitating cognitive deficits in the novel object recognition test. Subcellular fractionation, combined with proteome and phosphoproteome analysis revealed the developing synapse is profoundly vulnerable to SD, whereas adults exhibit comparative resilience. SD in juveniles, and not older mice, aberrantly drives induction of synapse potentiation, synaptogenesis, and expression of peri-neuronal nets. Our analysis further reveals the developing synapse as a convergent node between vulnerability to SD and ASD genetic risk. Together, our systematic analysis supports a distinct developmental function of sleep and reveals how sleep disruption impacts key aspects of brain development, providing mechanistic insights for ASD susceptibility.

Early life sleep disruption potentiates lasting sex-specific changes in behavior in genetically vulnerable Shank3 heterozygous autism model mice.

BACKGROUND: Patients with autism spectrum disorder (ASD) experience high rates of sleep disruption beginning early in life; however, the developmental consequences of this disruption are not understood. We examined sleep behavior and the consequences of sleep disruption in developing mice bearing C-terminal truncation mutation in the high-confidence ASD risk gene SHANK3 (Shank3ΔC). We hypothesized that sleep disruption may be an early sign of developmental divergence, and that clinically relevant Shank3WT/ΔC mice may be at increased risk of lasting deleterious outcomes following early life sleep disruption. METHODS: We recorded sleep behavior in developing Shank3ΔC/ΔC, Shank3WT/ΔC, and wild-type siblings of both sexes using a noninvasive home-cage monitoring system. Separately, litters of Shank3WT/ΔC and wild-type littermates were exposed to automated mechanical sleep disruption for 7 days prior to weaning (early life sleep disruption: ELSD) or post-adolescence (PASD) or undisturbed control (CON) conditions. All groups underwent standard behavioral testing as adults. RESULTS: Male and female Shank3ΔC/ΔC mice slept significantly less than wild-type and Shank3WT/ΔC siblings shortly after weaning, with increasing sleep fragmentation in adolescence, indicating that sleep disruption has a developmental onset in this ASD model. ELSD treatment interacted with genetic vulnerability in Shank3WT/ΔC mice, resulting in lasting, sex-specific changes in behavior, whereas wild-type siblings were largely resilient to these effects. Male ELSD Shank3WT/ΔC subjects demonstrated significant changes in sociability, sensory processing, and locomotion, while female ELSD Shank3WT/ΔC subjects had a significant reduction in risk aversion. CON Shank3WT/ΔC mice, PASD mice, and all wild-type mice demonstrated typical behavioral responses in most tests. LIMITATIONS: This study tested the interaction between developmental sleep disruption and genetic vulnerability using a single ASD mouse model: Shank3ΔC (deletion of exon 21). The broader implications of this work should be supported by additional studies using ASD model mice with distinct genetic vulnerabilities. CONCLUSION: Our study shows that sleep disruption during sensitive periods of early life interacts with underlying genetic vulnerability to drive lasting and sex-specific changes in behavior. As individuals progress through maturation, they gain resilience to the lasting effects of sleep disruption. This work highlights developmental sleep disruption as an important vulnerability in ASD susceptibility.

Bilateral brain activity in auditory regions is necessary for successful vocal learning in songbirds.

In humans and songbirds, neuronal activation for language and song shifts from bilateral- or diffuse-activation to left-hemispheric dominance while proficiency increases. Further parallels exist at the behavioural level: unstructured juvenile vocalizations become highly stereotyped adult vocalizations through a process of trial and error learning. Greater left-hemispheric dominance in the songbird caudomedial Nidopallium (NCM), a Wernicke-like region, is related to better imitation of the tutor's song learned early in development, indicating a role for the left NCM in forming auditory memories. Here, we hypothesize that inhibition of the left NCM during interaction with a song tutor would impair imitation of the tutor's song more than inhibition of the right NCM. We infused a transient sodium channel blocker (TTX) immediately prior to tutoring sessions in either the left or right auditory lobule of previously isolated juvenile male zebra finches (Taeniopygia guttata). Upon maturation, both right-infused and left-infused birds' tutor song imitation was significantly impaired. Left-infused birds also showed less consistency in the rhythmic stability of their song as well as increased pitch, suggesting a subtle division of function between the left and right auditory lobules.

Mania- and anxiety-like behavior and impaired maternal care in female diacylglycerol kinase eta and iota double knockout mice.

Genome-wide association studies linked diacylglycerol kinase eta and iota to mood disorders, including bipolar disorder and schizophrenia, and both genes are expressed throughout the brain. Here, we generated and behaviorally characterized female mice lacking Dgkh alone, Dgki alone, and double Dgkh/Dgki-knockout (dKO) mice. We found that fewer than 30% of newborn pups raised by dKO females survived to weaning, while over 85% of pups survived to weaning when raised by wild-type (WT) females. Poor survival under the care of dKO mothers was unrelated to pup genotype. Moreover, pups from dKO dams survived when fostered by WT dams, suggesting the poor survival rate of dKO-raised litters was related to impaired maternal care by dKO dams. Nest building was similar between WT and dKO dams; however, some dKO females failed to retrieve any pups in a retrieval assay. Pups raised by dKO dams had smaller or absent milk spots and reduced weight, indicative of impaired nursing. Unlike WT females, postpartum dKO females showed erratic, panicked responses to cage disturbances. Virgin dKO females showed behavioral signs of anxiety and mania, which were not seen in mice lacking either Dgkh or Dgki alone. Our research indicates that combined deletion of Dgkh and Dgki impairs maternal behavior in the early postpartum period, and suggests female dKO mice model symptoms of mania and anxiety.

Orexin-A hyperphagia: hindbrain participation in consummatory feeding responses.

Orexin-A (ORXA) is an orexigenic neuropeptide produced by the lateral hypothalamus that increases food intake when injected into the brain ventricles or forebrain nuclei. We used a licking microstructure analysis to evaluate hindbrain and forebrain ORXA effects in intact and hindbrain-lesioned rats, to identify the motivational and anatomical bases of ORXA hyperphagia. Intact rats with cannulas in the fourth brain ventricle (4V) received vehicle (artificial cerebrospinal fluid) or ORXA (0.1, 0.4, 1, or 10 nm) injections before 90 min access to 0.1 m sucrose. Meal size and frequency were increased in a double-dissociated manner by the 1 and 10 nm doses, respectively. In experiment 2, 4V 1 nm ORXA was applied to rats offered solutions varied in caloric and gustatory intensity (water and 0.1 and 1 m sucrose). ORXA increased meal frequency for all tastants. ORXA increased meal size only for 0.1 m sucrose, by prolonging the meal without affecting early ingestion rate or lick burst size, suggesting that 4V ORXA influenced inhibitory postingestive feedback rather than taste evaluation. In experiment 3, rats with cannulas in the third ventricle (3V) received dorsal medullary lesions centered on the area postrema (APX group) or sham procedures, and licking for water and 0.1 and 1 m sucrose was evaluated after 1 nm 3V ORXA/artificial cerebrospinal fluid injections. The 3V ORXA increased 0.1 m sucrose meal size and meal frequency for all tastants in the sham group, as observed after 4V ORXA in experiment 2. In the APX group, 3V ORXA injections influenced meal frequency, but they no longer increased meal size. However, the APX rats increased meal size for 0.1 m sucrose after food and water deprivation and after 3V angiotensin II injection. They also showed meal size suppression after 3V injection of the melanocortin-3/4 receptor agonist melanotan II (1 nm). These findings suggest that the area postrema and subjacent nucleus of the solitary tract are necessary for increases in consummatory (meal size) but not appetitive (meal frequency) responses to 3V ORXA. The meal size increases may be due to reduced postingestive feedback inhibition induced by ORXA delivered to either the hindbrain or forebrain ventricles.