Neuroscience
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Alterations in early environmental conditions that interfere with the creation of a stable mother-pup bond have been suggested to be a risk factor for the development of stress-related psychopathologies later in life. The long-lasting effects of early experiences are mediated by changes in various cerebral circuits, such as the corticolimbic system, which processes aversive and rewarding stimuli. However, it is evident that the early environment is not sufficient per se to induce psychiatric disorders; interindividual (eg, sex-based) differences in the response to environmental challenges exist. ⋯ To this end, we assessed the behavioral phenotype of RCF and control (male and female) mice in the saccharine preference test and cocaine-induced conditioned place preference to evaluate the response to natural and pharmacological stimuli and in the elevated plus maze test and forced swimming test to measure their anxiety- and depression-like behavior. We also evaluated FST-induced c-Fos immunoreactivity in various brain regions that are engaged in the response to acute stress exposure (FST). Notably, RCF has opposing effects on the adult response to these tests between sexes, directing male mice toward an "anhedonia-like" phenotype and increasing the sensitivity for rewarding stimuli in female mice.
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One deficit associated with schizophrenia (SZ) is the reduced ability to distinguish self-caused sensations from those due to external sources. This reduced sense of agency (SoA, subjective awareness of control over one's actions) is hypothesized to result from a diminished utilization of internal monitoring signals of self-movement (i.e., efference copy) which subsequently impairs forming and utilizing sensory prediction errors (differences between the predicted and actual sensory consequences resulting from movement). Another important function of these internal monitoring signals is the facilitation of higher-order mechanisms related to motor learning and control. ⋯ Although adaptation was similar for SZP and controls, the extent of generalization was significantly less for SZP; movement trajectories made by patients to the furthest untrained target (135o) before and after adaptation were largely indistinguishable. Interestingly, deficits in generalization were correlated with positive symptoms of psychosis in SZP (e.g., hallucinations). Generalization was also associated with measures of SoA across both SZP and HC, emphasizing the role action awareness plays in motor behavior, and suggesting that misattributing agency, even in HC, manifests in abnormal motor performance.
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Accumulating evidence indicates that phosphorylated serum- and glucocorticoid-regulated kinase 1 (SGK1) is associated with spinal nociceptive sensitization by modulating glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined whether spinal SGK1 signaling contributes to the development of morphine analgesic tolerance. Chronic morphine administration markedly induced phosphorylation of SGK1 in the spinal dorsal horn neurons. ⋯ Finally, spinal delivery of SGK1 small interfering RNA exhibited similar inhibitory effects on morphine-induced tolerance, phosphorylation of NF-κB p65, as well as upregulation of NR1 and NR2B expression. Our findings demonstrate that spinal SGK1 contributes to the development of morphine tolerance by enhancing NF-κB p65/NMDAR signaling. Interfering spinal SGK1 signaling pathway could be a potential strategy for prevention of morphine tolerance in chronic pain management.
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Glutamate is the major excitatory neurotransmitter in the brain and plays an essential role in regulating wakefulness. Histaminergic neurons, which are exclusively localized in the tuberomammillary nucleus (TMN) of the hypothalamus, have a pivotal role in the regulation of sleep-wake patterns by sending widespread projections into many brain areas implicated in sleep-wake control. The role of glutamate in histaminergic neurons within the TMN and the resulting sleep-wake profile remains unknown. ⋯ The arousal-promoting effect of glutamate was inhibited by NMDA and histamine H1 receptor antagonists. Furthermore, MK-801, an NMDA receptor antagonist, inhibited the firing rate of histaminergic neurons and increased non-rapid eye movement sleep after microinjection into rat TMN. Taken together, these findings demonstrated that glutamate activated histaminergic neurons in the TMN and increased wakefulness in rats, possibly via the action of NMDA and histamine H1 receptors.
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Orofacial and somatic disgust reactions are observed in rats following intraoral infusion of not only bitter quinine (innate disgust) but also sweet saccharin previously paired with illness (learned disgust). It remains unclear, however, whether these innate and learned disgust reactions share a common neural basis and which brain regions, if any, host it. In addition, there is no established method to genetically access neurons whose firing is associated with disgust (disgust-associated neurons). ⋯ In addition, TRAP following quinine infusion (Quinine-TRAP) resulted in significantly more YFP-positive neurons in the IPAC, compared to TRAP following water infusion. A significant number of the YFP-positive neurons following Quinine-TRAP were co-labeled with Arc following the second quinine infusion, confirming that Quinine-TRAP preferentially labeled quinine-activated neurons in the IPAC. Our results suggest that the IPAC activity is associated with both innate and learned disgust and that disgust-associated neurons in the IPAC are genetically accessible by TRAP.