Acute sleep deprivation reduces fear memories in male and female mice.

Sleep problems are a prominent feature of mental health conditions including post-traumatic stress disorder (PTSD). Despite its potential importance, the role of sleep in the development of and/or recovery from trauma-related illnesses is not understood. Interestingly, there are reports that sleep deprivation immediately after a traumatic experience can reduce fear memories, an effect that could be utilized therapeutically in humans. While the mechanisms of this effect are not completely understood, one possible explanation for these findings is that immediate sleep deprivation interferes with consolidation of fear memories, rendering them weaker and more sensitive to intervention. Here, we allowed fear-conditioned mice to sleep immediately after fear conditioning during a time frame (18 hr) that includes and extends beyond periods typically associated with memory consolidation before subjecting them to 6 hr of sleep deprivation. Mice deprived of sleep with this delayed regimen showed dramatic reductions in fear during tests conducted immediately after sleep deprivation, as well as 24 hr later. This sleep deprivation regimen also increased levels of mRNA encoding brain-derived neurotrophic factor (BDNF), a molecule implicated in neuroplasticity, in the basolateral amygdala (BLA), a brain area implicated in fear and its extinction. These findings raise the possibility that the effects of our delayed sleep deprivation regimen are not due to disruption of memory consolidation, but instead are caused by BDNF-mediated neuroadaptations within the BLA that actively suppress expression of fear. Treatments that safely reduce expression of fear memories would have considerable therapeutic potential in the treatment of conditions triggered by trauma.

Differential effects of the stress peptides PACAP and CRF on sleep architecture in mice.

Stress produces profound effects on behavior, including persistent alterations in sleep patterns. Here we examined the effects of two prototypical stress peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing factor (CRF), on sleep architecture and other translationally-relevant endpoints. Male and female mice were implanted with subcutaneous transmitters enabling continuous measurement of electroencephalography (EEG) and electromyography (EMG), as well as body temperature and locomotor activity, without tethering that restricts free movement, body posture, or head orientation during sleep. At baseline, females spent more time awake (AW) and less time in slow wave sleep (SWS) than males. Mice then received intracerebral infusions of PACAP or CRF at doses producing equivalent increases in anxiety-like behavior. The effects of PACAP on sleep architecture were similar in both sexes and resembled those reported in male mice after chronic stress exposure. Compared to vehicle infusions, PACAP infusions decreased time in AW, increased time in SWS, and increased rapid eye movement sleep (REM) time and bouts on the day following treatment. In addition, PACAP effects on REM time remained detectable a week after treatment. PACAP infusions also reduced body temperature and locomotor activity. Under the same experimental conditions, CRF infusions had minimal effects on sleep architecture in either sex, causing only transient increases in SWS during the dark phase, with no effects on temperature or activity. These findings suggest that PACAP and CRF have fundamentally different effects on sleep-related metrics, and provide new insights into the mechanisms by which stress disrupts sleep.

Stress Diminishes BDNF-stimulated TrkB Signaling, TrkB-NMDA Receptor Linkage and Neuronal Activity in the Rat Brain.

Exposure to intense or repeated stressors can lead to depression or post-traumatic stress disorder (PTSD). Neurological changes induced by stress include impaired neurotrophin signaling, which is known to influence synaptic integrity and plasticity. The present study used an ex vivo approach to examine the impact of acute or repeated stress on BDNF-stimulated TrkB signaling in hippocampus (HIPPO) and prefrontal cortex (PFC). Rats in an acute multiple stressor group experienced five stressors in one day whereas rats in a repeated unpredictable stressor group experienced 20 stressors across 10 days. After stress exposure, slices were incubated with vehicle or BDNF, followed by immunoprecipitation and immunoblot assays to assess protein levels, activation states and protein-protein linkage associated with BDNF-TrkB signaling. Three key findings are (1) exposure to stressors significantly diminished BDNF-stimulated TrkB signaling in HIPPO and PFC such that reductions in TrkB activation, diminished recruitment of adaptor proteins to TrkB, reduced activation of downstream signaling molecules, disruption of TrkB-NMDAr linkage, and changes in basal and BDNF-stimulated Arc expression were observed. (2) After stress, BDNF stimulation enhanced TrkB-NMDAr linkage in PFC, suggestive of compensatory mechanisms in this region. (3) We discovered an uncoupling between TrkB signaling, TrkB-NMDAr linkage and Arc expression in PFC and HIPPO. In addition, a robust surge in pro-inflammatory cytokines was observed in both regions after repeated exposure to stressors. Collectively, these data provide therapeutic targets for future studies that investigate how to reverse stress-induced downregulation of BDNF-TrkB signaling and underscore the need for functional studies that examine stress-related TrkB-NMDAr activities in PFC.

Appetitive and aversive sensory preconditioning in rats is impaired by disruption of the postrhinal cortex.

Episodic memory involves binding stimuli and/or events together in time and place. Furthermore, memories become more complex when new experiences influence the meaning of stimuli within the original memory. Thus collectively, complex episodic memory formation and maintenance involves processes such as encoding, storage, retrieval, updating and reconsolidation, which can be studied using animal models of higher-order conditioning. In the present study aversive and appetitive sensory preconditioning paradigms were used to test the hypothesis that the postrhinal cortex (POR), which is a component of the hippocampal memory system, is involved in higher-order conditioning. Drawing on the known role of the POR in contextual learning, Experiment 1 employed a four-phase sensory preconditioning task that involved fear learning and context discrimination in rats with or without permanent lesions of the POR. In parallel, to examine POR function during higher-order conditioning in the absence of a particular spatial arrangement, Experiments 2 and 3 used a three-phase sensory preconditioning paradigm involving phasic stimuli. In Experiment 2, bilateral lesions of the POR were made and in Experiment 3, a chemogenetic approach was used to temporarily inactivate POR neurons during each phase of the paradigm. Evidence of successful sensory preconditioning was observed in sham rats which, during the critical context discrimination test, demonstrated higher levels of freezing behavior when re-exposed to the paired versus the unpaired context, whereas POR-lesioned rats did not. Data from the appetitive sensory preconditioning paradigm also confirmed the hypothesis in that during the critical auditory discrimination test, sham rats showed greater food cup responding following presentations of the paired compared to the unpaired auditory stimulus, whereas POR-lesioned rats did not. Lastly, in Experiment 3, when the POR was inactivated only during preconditioning or only during conditioning, discrimination during the critical auditory test was impaired. Thus, regardless of whether stimulus-stimulus associations were formed between static or phasic stimuli or whether revaluation of the paired stimulus occurred through association with an aversive or an appetitive unconditioned stimulus, the effects were the same; POR lesions disrupted the ability to use higher-order conditioned stimuli to guide prospective behavior.