Neuroscience
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The transient receptor potential A1 (TRPA1) channel contributes to nociceptive signaling in certain pain models. It has been suggested that Ca(2+), which activates and modulates TRPA1, could play a critical regulatory role in this process. Since TRPA1 and transient receptor potential V1 (TRPV1) channels are co-expressed and interact in neurons, we investigated whether activation and modulation of TRPA1 by Ca(2+) is regulated by TRPV1. ⋯ First it was demonstrated that the mutations in TRPV1 did not affect association of the TRPA1 and TRPV1 channels. However, these TRPV1 mutations, particularly Y671K, altered the following characteristics of TRPA1: magnitude of I(MO) in presence and absence of [Ca(2+)](e); the influence of [Ca(2+)](e) on the voltage-dependency of I(MO), and open probability of single-channel I(MO). In summary, activation of TRPA1 by [Ca(2+)](e) and [Ca(2+)](i) is controlled by the TRPV1 channel, and characteristics of I(MO) depend on Ca(2+) permeability of the TRPV1 channel.
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Hyperalgesia in animal injury models is linked to activation of descending raphespinal modulatory circuits originating in the rostral ventromedial medulla (RVM). A neurokinin-1 (NK-1) receptor antagonist microinjected into the RVM before or after inflammation produced by complete Freund's adjuvant (CFA) resulted in an attenuation of thermal hyperalgesia. A transient (acute) or a continuous infusion of Substance P (SP) microinjected into the RVM of non-inflamed animals led to similar pain hypersensitivity. ⋯ Following a low dose of SP infused into the RVM, intrathecal muscimol (GABA(A) agonist) increased SP-induced thermal hyperalgesia, phosphorylated NKCC1 protein expression, and NMDA NR1 subunit phosphorylation in the spinal cord. The thermal hyperalgesia was blocked by intrathecal gabazine, the GABA(A) receptor antagonist, and MK-801, the NMDA receptor channel blocker. These findings indicate that NK-1 receptors in the RVM are involved in SP-induced thermal hyperalgesia, this hyperalgesia is 5-HT3-receptor dependent at the spinal level, and involves the functional interaction of spinal GABA(A) and NMDA receptors.
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The Ts65Dn (TS) mouse is the most widely used model of Down syndrome (DS). This mouse shares many phenotypic characteristics with the human condition including cognitive and neuromorphological alterations. In this study the effects of physical exercise on hippocampal neurogenesis and behavior in TS mice were assessed. 10-12 month-old male TS and control (CO) mice were submitted to voluntary physical exercise for 7 weeks and the effects of this protocol on hippocampal morphology, neurogenesis and apoptosis were evaluated. ⋯ Voluntary physical exercise did not rescue these alterations in TS mice but it did increase the number of doublecortin (DCX)-and phospho histone 3 (PH3)-positive neurons in CO mice. It is concluded that physical exercise produced a modest anxiolytic effect in CO mice and that this was accompanied by an increased number of immature cells in the hippocampal DG. On the other hand, voluntary physical exercise exerted a positive effect on TS mice learning of the platform position in the Morris water maze that seems to be mediated by a neurogenesis-independent mechanism.
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Environmental enrichment (EE) introduced during abstinence from cocaine self-administration is protective in reducing cue-elicited incentive motivation for cocaine in rats. This study examined neural activation associated with this protective effect of EE using Fos protein expression as a marker. Rats were trained to press a lever reinforced by cocaine (0.75 mg/kg/0.1 mL infusion) and light and tone cues across 15 consecutive days during which they were all housed in isolated conditions (IC). ⋯ In contrast, IC enhanced Fos expression in the dorsal caudate putamen, substantia nigra, and central amygdala, evident as an increase relative to both PC and EE. These results suggest that EE blunts neural activation throughout the mesocorticolimbic circuitry involved in cue-elicited incentive motivation for cocaine, whereas IC enhances activation primarily within the nigrostriatal dopamine pathway. These findings have important implications for understanding and treating drug-conditioned craving in humans.
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Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that displays robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including low social interactions, reduced vocalizations in social settings, and high levels of repetitive self-grooming. Autism-relevant phenotypes in BTBR offer translational tools to discover neurochemical mechanisms underlying unusual mouse behaviors relevant to symptoms of autism. ⋯ BTBR displayed less reactivity than B6 to a noxious thermal stimulus in the hot plate, and less immobility than B6 in both the forced swim and tail suspension depression-related tasks. BTBR, therefore, exhibited lower depression-like scores than B6 on two standard tests sensitive to antidepressants, did not differ from B6 on two well-validated anxiety-like behaviors, and did not exhibit unusual stress reactivity to sensory stimuli. Our findings support the interpretation that autism-relevant social deficits, vocalizations, and repetitive behaviors are not the result of abnormal stress reactivity in the BTBR mouse model of autism.