Sex-biased effects of outcome devaluation by sensory-specific satiety on Pavlovian-conditioned behavior.

Goal-directed behavior relies on accurate mental representations of the value of expected outcomes. Disruptions to this process are a central feature of several neuropsychiatric disorders, including addiction. Goal-directed behavior is most frequently studied using instrumental paradigms paired with outcome devaluation, but cue-evoked behaviors in Pavlovian settings can also be goal-directed and therefore sensitive to changes in outcome value. Emerging literature suggests that male and female rats may differ in the degree to which their Pavlovian-conditioned responses are goal-directed, but interpretation of these findings is complicated by the tendency of female and male rats to engage in distinct types of Pavlovian responses when trained with localizable cues. Here, we used outcome devaluation via sensory-specific satiety to assess the behavioral responses in male and female Long Evans rats trained to respond to an auditory CS (conditioned stimulus) in a Pavlovian-conditioning paradigm. We found that satiety-induced devaluation led to a decrease in behavioral responding to the reward-predictive CS, with males showing an effect on both port entry latency and probability and females showing an effect only on port entry probability. Overall, our results suggest that outcome devaluation affects Pavlovian-conditioned responses in both male and female rats, but that females may be less sensitive to outcome devaluation.

Outcome devaluation by sensory-specific satiety alters Pavlovian-conditioned behavior in male and female rats.

Goal-directed behavior relies on accurate mental representations of the value of expected outcomes. Disruptions to this process are a central feature of several neuropsychiatric disorders, including addiction. Goal-directed behavior is most frequently studied using instrumental paradigms paired with outcome devaluation, but cue-evoked behaviors in Pavlovian settings can also be goal-directed and therefore sensitive to changes in outcome value. Emerging literature suggests that male and female rats may differ in the degree to which their Pavlovian-conditioned responses are goal-directed, but interpretation of these findings is complicated by the tendency of female and male rats to engage in distinct types of Pavlovian responses when trained with localizable cues. Here, we used outcome devaluation via sensory-specific satiety to assess the behavioral responses in male and female Long Evans rats trained to respond to an auditory CS (conditioned stimulus) in a Pavlovian-conditioning paradigm. We found that satiety-induced devaluation led to a decrease in behavioral responding to the reward-predictive CS, with males showing an effect on both port entry latency and probability and females showing an effect only on port entry probability. Overall, our results suggest that outcome devaluation affects Pavlovian-conditioned responses in both male and female rats, but that females may be less sensitive to outcome devaluation.

Acute immobilization stress evokes sexually dimorphic peripheral and hippocampal neuroimmune responses in adult rats.

Stress perception and response vary across sexes and may contribute to the sex differences in susceptibility to psychopathology. Stress also engages the immune system and baseline immune system markers are known to be sexually dimorphic. Here, we investigated if the neuroimmune consequences following a single episode of acute immobilization stress (AIS) are sexually dimorphic in male and female Sprague-Dawley rats. We analyzed immune parameters in the periphery, and markers of neuroinflammation in the hippocampus, a key target of stress effects in the brain. We observed sexual dimorphism in the pattern of regulation of peripheral cytokines following stress, with males showing a significant increase in the levels of specific cytokines compared to females. Hippocampal cytokine and neuroinflammation-associated gene expression level analysis did not reveal any sexually dimorphic effects of AIS. However, we noted lower baseline expression levels for specific cytokines and many of the genes analyzed in the hippocampus of control females compared to control males. Finally, we assessed the levels of components of the NLRP3 inflammasome in the hippocampus and observed increased NLRP3 protein levels at baseline in females. We further noted that while males showed an increase in NLRP3 levels following AIS, females failed to show a similar change. Together, our results highlight a sexual dimorphism in neuroimmune consequences following AIS, both in the periphery and within the hippocampus, with males displaying robust proinflammatory changes and similar changes not observed in females. Our study underlines the importance of investigating the effect of sex on neuroimmune consequences following acute stress.

Acute pharmacogenetic activation of medial prefrontal cortex excitatory neurons regulates anxiety-like behaviour.

The medial prefrontal cortex (mPFC) is implicated in anxiety-like behaviour. In rodent models, perturbations of mPFC neuronal activity through pharmacological manipulations, optogenetic activation of mPFC neurons or cell-type specific pharmacogenetic inhibition of somatostatin interneurons indicate conflicting effects on anxiety-like behaviour. In the present study we examined the effects of pharmacogenetic activation of Ca 2+/calmodulin-dependent protein kinase alpha (CamKII alpha)-positive excitatory neurons on anxiety-like behaviour. We used clozapine-N-oxide (CNO) to pharmacogenetically activate virally delivered CamKII alpha-hM3Dq-DREADD in mPFC excitatory neurons. The effects of acute CNO or vehicle treatment on anxiety-like behaviour in the open field and elevated plus maze tests were examined in rats virally infected with either CamKII alpha-hM3Dq-DREADD or CamKII alpha-GFP. In addition, the effects of acute CNO treatment on the expression of the neuronal activity marker c-Fos were examined in the mPFC as well as downstream target neuronal circuits using immunohistochemistry. Acute pharmacogenetic activation of mPFC excitatory neurons evoked a significant decrease in anxiety-like behaviour selectively on the elevated plus maze task, but not the open field test. Acute CNO treatment resulted in enhanced c-Fos-immunopositive cell number in the infralimbic, prelimbic and cingulate subdivisions of the mPFC. This was also accompanied by enhanced c-Fos-immunopositive cell number in multiple downstream circuits of the mPFC in CNO-treated hM3Dq animals. Acute pharmacogenetic activation of mPFC excitatory neurons reduces anxietylike behaviour in a task-specific fashion accompanied by enhanced c-Fos expression in the mPFC and multiple target circuits implicated in the regulation of anxiety-like behaviour.

Acute stress evokes sexually dimorphic, stressor-specific patterns of neural activation across multiple limbic brain regions in adult rats.

Stress enhances the risk for psychiatric disorders such as anxiety and depression. Stress responses vary across sex and may underlie the heightened vulnerability to psychopathology in females. Here, we examined the influence of acute immobilization stress (AIS) and a two-day short-term forced swim stress (FS) on neural activation in multiple cortical and subcortical brain regions, implicated as targets of stress and in the regulation of neuroendocrine stress responses, in male and female rats using Fos as a neural activity marker. AIS evoked a sex-dependent pattern of neural activation within the cingulate and infralimbic subdivisions of the medial prefrontal cortex (mPFC), lateral septum (LS), habenula, and hippocampal subfields. The degree of neural activation in the mPFC, LS, and habenula was higher in males. Female rats exhibited reduced Fos positive cell numbers in the dentate gyrus hippocampal subfield, an effect not observed in males. We addressed whether the sexually dimorphic neural activation pattern noted following AIS was also observed with the short-term stress of FS. In the paraventricular nucleus of the hypothalamus and the amygdala, FS similar to AIS resulted in robust increases in neural activation in both sexes. The pattern of neural activation evoked by FS was distinct across sexes, with a heightened neural activation noted in the prelimbic mPFC subdivision and hippocampal subfields in females and differed from the pattern noted with AIS. This indicates that the sex differences in neural activation patterns observed within stress-responsive brain regions are dependent on the nature of stressor experience.

Early emergence of altered 5-HT2A receptor-evoked behavior, neural activation and gene expression following maternal separation.

The early stress of Maternal Separation (MS) contributes to the establishment of adult psychopathology. The serotonergic (5-HT) system is implicated during this temporal window in mediating the development of mood-related behaviors. MS is reported to evoke altered 5-HT2A receptor function in adulthood. However, the ontogeny of altered 5-HT2A receptor responsivity following MS remains unknown. Here, we examined 5-HT2A receptor agonist, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) (2mg/kg) evoked responses, namely stereotypical head-twitch behaviors in control and MS Sprague-Dawley rat pups at postnatal day 21 (P21). MS involved a separation of pups from the dam for 3h daily from postnatal day 2-14. MS pups at P21 exhibited significantly enhanced head-twitch behaviors compared to controls. Using c-Fos cell counting we examined neural activation in control and MS pups following DOI treatment. MS pups exhibited altered DOI-evoked c-Fos expression within all mPFC subdivisions, but not in the hippocampus, lateral septum and hypothalamus, suggesting differential prefrontal neural activation upon 5-HT2A receptor stimulation following early stress. Gene profiling of 5-HT2A receptor-regulated immediate early genes (IEGs) indicated a decline in the expression of Fos, Fra1 and Egr1 mRNA under baseline conditions in the mPFC of MS pups. MS pups also showed an altered pattern in the regulation of several 5-HT2A receptor-regulated IEGs (Fos, Fra1, Bdnf, Egr1, Egr3) following DOI treatment. Collectively, these results highlight an early emergence of altered 5-HT2A receptor-evoked behavioral responses and neural activation patterns in multiple brain regions in animals with a history of MS.

Lifetime prevalence of and factors associated with non-traumatic musculoskeletal pains amongst surgeons and patients.

PURPOSE: There is evidence that surgeons make different recommendations for people seeking their care than they make for themselves. There may also be differences in pain episodes and management strategies between surgeons and people seeking care, knowledge of which might improve care. We aimed to assess whether the prevalence of non-traumatic pains, treatments and other factors differed between patients and surgeons. MATERIALS AND METHODS: Two-hundred and twenty surgeons, members of the Science of Variation Group (SOVG), and 248 patients seeking care at the Hand Service at a large academic hospital completed a survey regarding the lifetime incidence of non-traumatic pains lasting > one month using short versions of the Pain Catastrophising Scale (PCS-4); Patient Health Questionnaire (PHQ-2); and Short Health Anxiety Inventory (SHAI-5). RESULTS: Surgeons had a higher prevalence of at least one non-traumatic pain than patients and were more likely to report pain at more than one anatomical site. Patients were more likely to receive any treatment: surgery; injection; non-opioid medication; opioid medication; physical or occupational therapy. Patients missed work more often than surgeons. Age was the only factor independently associated with patient pain. Practicing in the United States was the only factor independently associated with surgeon pain. CONCLUSIONS: Non-traumatic pains are extremely common. Surgeons have particularly effective coping strategies, allowing them to maintain their life roles with limited medical care when in pain. Increasing the appeal and availability of methods for optimising coping strategies might help to narrow the gap between surgeon and patient health.

Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior.

Cerebral malaria is associated with cerebrovascular damage and neurological sequelae. However, the neurological consequences of uncomplicated malaria, the most prevalent form of the disease, remain uninvestigated. Here, using a mild malaria model, we show that a single Plasmodium chabaudi adami infection in adult mice induces neuroinflammation, neurogenic, and behavioral changes in the absence of a blood-brain barrier breach. Using cytokine arrays we show that the infection induces differential serum and brain cytokine profiles, both at peak parasitemia and 15days post-parasite clearance. At the peak of infection, along with the serum, the brain also exhibited a definitive pro-inflammatory cytokine profile, and gene expression analysis revealed that pro-inflammatory cytokines were also produced locally in the hippocampus, an adult neurogenic niche. Hippocampal microglia numbers were enhanced, and we noted a shift to an activated profile at this time point, accompanied by a striking redistribution of the microglia to the subgranular zone adjacent to hippocampal neuronal progenitors. In the hippocampus, a distinct decline in progenitor turnover and survival was observed at peak parasitemia, accompanied by a shift from neuronal to glial fate specification. Studies in transgenic Nestin-GFP reporter mice demonstrated a decline in the Nestin-GFP(+)/GFAP(+) quiescent neural stem cell pool at peak parasitemia. Although these cellular changes reverted to normal 15days post-parasite clearance, specific brain cytokines continued to exhibit dysregulation. Behavioral analysis revealed selective deficits in social and anxiety-like behaviors, with no change observed in locomotor, cognitive, and depression-like behaviors, with a return to baseline at recovery. Collectively, these findings indicate that even a single episode of mild malaria results in alterations of the brain cytokine profile, causes specific behavioral dysfunction, is accompanied by hippocampal microglial activation and redistribution, and a definitive, but transient, suppression of adult hippocampal neurogenesis.