Ultrasonic vocalization sex differences in 5-HT1A-R deficient mouse pups: Predictive phenotypes associated with later-life anxiety-like behaviors.

Anxiety disorders affect nearly twice as many women as men. However, little is known regarding sex-dependent developmental behavioral differences and whether there is an association with later life anxiety disorders. The present study assessed the developmental-behavioral milestones (DBMs) and their relationship with later life anxiety-like behaviors by comparing postnatal ultrasonic vocalizations (USVs) with open field (OF), elevated plus maze (EPM), and light/dark (LD) anxiety test outcomes using the serotonin 1A receptor knockout (KO) mouse model of anxiety. The USVs and DBMs (i.e., grasping, righting, and startle reflexes) were examined on postnatal day 6 (P6), P8, and P10. Adult anxiety-like behaviors were examined on P60 to compare the genotype and sex-dependent differences in anxiety-like behaviors and to correlate them with the USVs. The total number of USVs observed on P8 correlated with later life anxiety-like behaviors in a genotype-, age-, and sex-dependent manner. Interestingly, female KO (KOF) mice exhibited elevated levels of anxiety-like behavior within the OF, EPM, and LD tests. Additionally, an investigation of the USV subtypes, as well as USV sequence structure and repertoire variation, revealed that the KOF mice produced less complex USVs and complex USV-containing sequences on P10. The present study provides an intriguing, predictive "P8/10-USV-to-P60" anxiety-like behavioral model that may prove useful in future characterization, psychopharmacology, and drug rescue studies directed towards sex-specific anxiety treatment.

Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior.

Type IV ATPases are putative aminophospholipid translocases (APLTs), more commonly known as flippases. A pronounced induction of the flippase Atp8a1 was observed in post-mortem tissue homogenates from the hippocampus and temporal lobe of juvenile autistic subjects compared to age-matched controls. In order to simulate the human data, C57BL/6 mice were allowed to develop after intra-hippocampal injection of recombinant lentivirus expressing Atp8a1 at the early developmental stage of postnatal day 6 (P6). Transmission electron microscopy (TEM) analysis of the lentivirus-Atp8a1 treated (Atp8a1+) mice in adulthood revealed fewer and weaker excitatory synapses in the hippocampal CA1 region compared to mice injected with empty virus. Significant inhibition of the Schaffer collateral pathway was observed in the Atp8a1+ mice in paired-pulse recording (PPR) at 20-ms inter-stimulus interval. In the three-chambered sociability test, the Atp8a1+ mice displayed no preference for an encaged stranger mouse over a novel object, which is a characteristic autistic-like behavior. In sharp contrast, Atp8a1 (-/-) mice displayed a preference for a stranger mouse over the novel object, which is characteristic of neurotypical mouse behavior. However, similar to the Atp8a1+ mice, the Atp8a1 (-/-) mice harbored fewer and weaker excitatory synapses in CA1 compared to wild-type controls, and displayed inhibition at 20-ms inter-stimulus interval in PPR. These findings suggest that both elevated and diminished levels of Atp8a1 during early development are detrimental to brain connectivity, but only elevated Atp8a1 is associated with aberrant social behavior. Mice with augmented levels of Atp8a1 may therefore serve as a potential model in autism research.

Spinal cord stimulation protects against atrial fibrillation induced by tachypacing.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to modulate atrial electrophysiology and confer protection against ischemia and ventricular arrhythmias in animal models. OBJECTIVE: To determine whether SCS reduces the susceptibility to atrial fibrillation (AF) induced by tachypacing (TP). METHODS: In 21 canines, upper thoracic SCS systems and custom cardiac pacing systems were implanted. Right atrial and left atrial effective refractory periods were measured at baseline and after 15 minutes of SCS. Following recovery in a subset of canines, pacemakers were turned on to induce AF by alternately delivering TP and searching for AF. Canines were randomized to no SCS therapy (CTL) or intermittent SCS therapy on the initiation of TP (EARLY) or after 8 weeks of TP (LATE). AF burden (percent AF relative to total sense time) and AF inducibility (percentage of TP periods resulting in AF) were monitored weekly. After 15 weeks, echocardiography and histology were performed. RESULTS: Effective refractory periods increased by 21 ± 14 ms (P = .001) in the left atrium and 29 ± 12 ms (P = .002) in the right atrium after acute SCS. AF burden was reduced for 11 weeks in EARLY compared with CTL (P <.05) animals. AF inducibility remained lower by week 15 in EARLY compared with CTL animals (32% ± 10% vs 91% ± 6%; P <.05). AF burden and inducibility were not significantly different between LATE and CTL animals. There were no structural differences among any groups. CONCLUSIONS: SCS prolonged atrial effective refractory periods and reduced AF burden and inducibility in a canine AF model induced by TP. These data suggest that SCS may represent a treatment option for AF.