Neuroscience
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Classical fear conditioning is believed to result from potentiation of conditioned synaptic inputs in the basolateral amygdala. That is, the conditioned stimulus would excite more neurons in the central nucleus and, via their projections to the brainstem and hypothalamus, evoke fear responses. However, much data suggests that extinction of fear responses does not depend on the reversal of these changes but on a parallel NMDA-dependent learning that competes with the first one. ⋯ Depotentiation of previously potentiated synapses did not revert the modification in paired pulse facilitation, suggesting that LTP is associated with presynaptic alterations, but that LTD and depotentiation depend on postsynaptic changes. Taken together, our results suggest that basolateral synapses onto intercalated neurons can express NMDA-dependent LTP and LTD, consistent with the possibility that intercalated neurons are a critical locus of plasticity for the extinction of conditioned fear responses. Ultimately, these plastic events may prevent conditioned amygdala responses from exciting neurons of the central nucleus, and thus from evoking conditioned fear responses.
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Physical dependence is a widely known consequence of morphine intake. Although commonly associated with prolonged or repeated morphine administration, withdrawal symptoms can be elicited even after a single prior morphine exposure. What remains contentious is the extent to which physical dependence following acute and chronic morphine treatment is mediated by common physiological substrates and, accordingly, represent distinct syndromes. ⋯ Substantial heritability was also observed for acute and both paradigms of chronic dependence, with estimates ranging from h(2)=0.53 to 0.70. The present demonstration of a strong genetic correlation between physical dependence to morphine following acute and chronic treatment implies that genes associated with variable sensitivity in the two traits are the same, and is suggestive of shared physiological substrates. The data also demonstrate that the differential genetic liability to morphine physical dependence begins with, and is predicted by, the first morphine exposure.
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Interleukin-6 (IL-6) is a multifunctional cytokine that may have a role in energy regulation. Using a recombinant adeno-associated viral vector expressing murine interleukin-6 (rAAV-IL-6), we examined the chronic effects of centrally expressed IL-6 on food intake, body weight and adiposity in male Sprague-Dawley rats, and investigated the underlying mechanisms. Direct delivery of rAAV-IL-6 into rat hypothalamus suppressed weight gain and visceral adiposity without affecting food intake over a 5-week period. rAAV-IL-6 enhanced uncoupling protein 1 (UCP1) protein levels in interscapular brown adipose tissue (BAT). ⋯ These data demonstrate that chronic elevation of IL-6 in the CNS reduces body weight gain and visceral adiposity without affecting food intake. The mechanism involves sympathetic induction of UCP1 in BAT and, presumably, enhanced thermogenesis in BAT. Furthermore, chronic central IL-6 stimulation desensitizes IL-6 signal transduction characterized by reversal of elevated P-STAT3 levels.
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Immobilization stress rapidly modulates BDNF mRNA expression in the hypothalamus of adult male rats.
We demonstrated that short times (15 min) of immobilization stress application induced a very rapid increase in brain-derived neurotrophic factor (BDNF) mRNA expression in rat hypothalamus followed by a BDNF protein increase. The early change in total BDNF mRNA level seems to reflect increased expression of the BDNF transcript containing exon III, which was also rapidly (15 min) modified. The paraventricular and supraoptic nuclei, two hypothalamic nuclei closely related to the stress response and known to express BDNF mRNA, were analyzed by in situ hybridization following immobilization stress. ⋯ In contrast, in the two other regions examined, the lateral and ventral magnocellular regions of the paraventricular nucleus, as well as in the supraoptic nucleus, signals above control were increased later, at 60 min. After stress application, plasma adrenocorticotropic hormone and corticosterone levels were strongly and significantly increased at 15 min. These studies demonstrated that immobilization stress challenge very rapidly enhanced BDNF mRNA levels as well as the protein, suggesting that BDNF may play a role in plasticity processes related to the stress response.
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There is a large body of data on the firing properties of dopamine cells in anaesthetised rats or rat brain slices. However, the extent to which these data relate to more natural conditions is uncertain, as there is little quantitative information available on the firing properties of these cells in freely moving rats. We examined this by recording from the midbrain dopamine cell fields using chronically implanted microwire electrodes. (1) In most cases, slowly firing cells with broad action potentials were profoundly inhibited by the dopamine agonist apomorphine, consistent with previously accepted criteria. ⋯ The distribution of burst incidence was similar to that previously reported with chloral hydrate anaesthesia, but the average intraburst frequency was higher in the conscious animal at rest and was higher again in bursts triggered by salient stimuli. (3) There was no evidence for spike frequency adaptation within bursts on average, consistent with the hypothesis that afterhyperpolarisation currents may be disabled during behaviourally induced bursting. (4) Presumed dopamine cells responded to reward-related stimuli with increased bursting rates and significantly higher intraburst frequencies compared to bursts emitted outside task context, indicating that modulation of afferent activity might not only trigger bursting, but may also regulate burst intensity. (5) In addition to the irregular single spike and bursting modes we found that extremely regular (clock-like) firing, previously only described for dopamine cells in reduced preparations, can also be expressed in the freely moving animal. (6) Cross-correlation analysis of activity recorded from simultaneously recorded neurones revealed coordinated activity in a quarter of dopamine cell pairs consistent with at least "functional" connectivity. On the other hand, most dopamine cell pairs showed no correlation, leaving open the possibility of functional sub-groupings within the dopamine cell fields. Taken together, the data suggest that the basic firing modes described for dopamine cells in reduced or anaesthetised preparations do reflect natural patterns of activity for these neurones, but also that the details of this activity are dependent upon modulation of afferent inputs by behavioural stimuli.