Neuroscience
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Emotional self-regulation plays a pivotal role in socialization and moral development. This capacity critically depends on the development of the prefrontal cortex (PFC). The present functional magnetic resonance imaging study was conducted to identify the neural circuitry underlying voluntary self-regulation of sadness in healthy girls (aged 8-10). ⋯ Significant loci of activations were also detected in the right anterior cingulate cortex (BA 24/32) and right ventrolateral PFC (BA 47). In an identical study previously conducted by our group in adult women [Biol Psychiatry 53 (2003) 502], reappraisal of sad film excerpts was associated with activation of the right OFC (BA 11) and right LPFC (BA 9). The greater number of prefrontal loci of activation found in children relative to adults during voluntary self-regulation of sadness may be related to the immaturity of the prefronto-limbic connections in childhood.
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We have investigated metaplasticity of the group I metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) and depotentiation (DP) induced by physiological synaptic stimulation in the medial perforant path of the dentate gyrus in vitro. Group I mGluR-LTD/DP was inhibited by prior preconditioning brief high frequency stimulation (HFS) if the preconditioning HFS induced long-term potentiation (LTP) or if the induction of LTP was inhibited by an NMDA receptor antagonist. ⋯ Activation of PKC was also necessary for the induction of mGluR-LTD itself, as the PKC inhibitor BIS prevented the induction of the mGluR-LTD. We suggest that the physiological stimulation of mGluRs by the preconditioning stimulation produces a PKC-dependent inactivation of subsequent group I mGluR functioning and thereby an inhibition of induction of group I mGluR-dependent LTD/DP induction.
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Although mu opioid receptors desensitize in various cell lines in vitro, the relationship of this change in signaling efficacy to the development of tolerance in vivo remains uncertain. It is clear that a system is needed in which functional mu opioid receptor expression is obtained in appropriate neurons so that desensitization can be measured, manipulated, and mutated receptors expressed in this environment. We have developed a recombinant system in which expression of a flag-tagged mu opioid receptor is returned to dorsal root ganglia neurons from mu opioid receptor knockout mice in vitro. ⋯ Both receptors desensitized equally over the first 6 h of DAMGO pre-incubation, but after 24 h the response of the endogenous receptor to DAMGO had desensitized further than the flag- tagged receptor (71+/-3 vs 29+/-7% respectively; P<0.002), indicating less desensitization in neurons expressing a higher density of receptor. Using flow cytometry to quantify the percentage of receptors remaining on the neuronal cell surface, the flag-tagged receptor internalized by 17+/-1% after 20 min and 55+/-2% after 24 h of DAMGO. These data indicate that this return of function model in neurons recapitulates many of the characteristics of endogenous mu opioid receptor function previously identified in non-neuronal cell lines.
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Comparative Study
Sex differences in the effect of ethanol injection and consumption on brain allopregnanolone levels in C57BL/6 mice.
The pharmacological profile of allopregnanolone, a neuroactive steroid that is a potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors, is similar to that of ethanol. Recent findings indicate that acute injection of ethanol increased endogenous allopregnanolone to pharmacologically relevant concentrations in male rats. However, there are no comparable data in mice, nor has the effect of ethanol drinking on endogenous allopregnanolone levels been investigated. ⋯ The sex differences in the effect of ethanol administration on endogenous allopregnanolone levels suggest that the hormonal milieu may impact ethanol's effect on GABAergic neurosteroids. Importantly, these data are the first to report the effect of ethanol drinking on allopregnanolone levels and indicate that ethanol consumption and ethanol injection can produce physiologically relevant allopregnanolone levels in male mice. These results have important implications for studies investigating the potential role of endogenous allopregnanolone levels in modulating susceptibility to ethanol abuse.
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Comparative Study
Pre- and post-synaptic effects of manipulating surface charge with divalent cations at the photoreceptor synapse.
Persistence of horizontal cell (HC) light responses in extracellular solutions containing low Ca2+ plus divalent cations to block Ca2+ currents (ICa) has been attributed to Ca2+-independent neurotransmission. Using a retinal slice preparation to record both ICa and light responses, we demonstrate that persistence of HC responses in low [Ca2+]o can instead be explained by a paradoxical increase of Ca2+ influx into photoreceptor terminals arising from surface charge-mediated shifts in ICa activation. Consistent with this explanation, application of Zn2+ or Ni2+ caused a hyperpolarizing block of HC light responses that was relieved by lowering [Ca2+]o. ⋯ Nominally divalent-free media produced inversion of HC light responses even though rod light responses remained hyperpolarizing; HC response inversion can be explained by surface charge-mediated shifts in ICa. In summary, HC light responses modifications induced by low divalent cation solutions can be explained by effects on photoreceptor light responses and membrane surface charge without necessitating Ca2+-independent neurotransmission. Furthermore, these results suggest that surface charge effects accompanying physiological changing divalent cation levels in the synaptic cleft may provide a means for modulating synaptic output from photoreceptors.