Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences. Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking. Here we use a rat model of compulsive drug seeking in which cocaine seeking persists in a subgroup of rats despite delivery of noxious foot shocks. We show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex, which was significantly more pronounced in compulsive drug-seeking animals. Furthermore, compensating for hypoactive prelimbic cortex neurons with in vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking. Our results show a marked reduction in prelimbic cortex excitability in compulsive cocaine-seeking rats, and that in vivo optogenetic prelimbic cortex stimulation decreased compulsive drug-seeking behaviours. Thus, targeted stimulation of the prefrontal cortex could serve as a promising therapy for treating compulsive drug use.
Neuropathic pain is a chronic pain that results from lesion or dysfunction of the nervous system. Depression and cognitive decline are often coupled to chronic pain, suggesting the involvement of cortical areas associated with higher cognitive functions. We investigated layer 2/3 pyramidal neurons in acute slices of the contralateral medial prefrontal cortex (mPFC) in the rat spared nerve injury (SNI) model of neuropathic pain and found morphological and functional differences between the mPFC of SNI and sham-operated animals. Basal, but not apical, dendrites of neurons from SNI rats are longer and have more branches than their counterparts in sham-operated animals; spine density is also selectively increased in basal dendrites of neurons from SNI rats; the morphological changes are accompanied by increased contribution to synaptic currents of the NMDA component. Interestingly, the NMDA/AMPA ratio of the synaptic current elicited in mPFC neurons by afferent fiber stimulation shows linear correlation with the rats' tactile threshold in the injured (but not in the contralateral) paw. Our results not only provide evidence that neuropathic pain leads to rearrangement of the mPFC, which may help defining the cellular basis for cognitive impairments associated with chronic pain, but also show pain-associated morphological changes in the cortex at single neuron level.T he prefrontal cortex (PFC) is associated with high-order cognitive and emotional functions including attention, decision making, goal-directed behavior, and working memory (1, 2). In humans, different subregions of the PFC have a role in acute pain; the medial prefrontal cortex (mPFC) was found to be involved in signaling the unpleasantness of pain (3); the anterior cingulate cortex mediates the affective component of pain responses (4) and the placebo effect (5); and anticipation of pain is positively correlated with activity in both the anterior cingulate and mPFC (6). Lending support to the hypothesis that chronic pain involves cortical reorganization, functional MRI (fMRI) studies in patients with complex region pain syndrome type I (CRPS-I) and back pain have shown that the patients' real-time rating of perceived intensity of spontaneous pain is associated with novel activity in mPFC (7, 8) when compared with activity patterns that correlate with rating of acute pain stimuli. Additionally, studies in humans with CRPS-I and chronic back pain demonstrate impaired performance on emotional decisionmaking tasks such as the Iowa Gambling Task (9), which implies involvement of the mPFC. Indeed, the performance of CRPS-I patients resembles that of patients with frontal cortex lesions. In patients with chronic back pain, the extent of activation of the mPFC during spontaneous pain and the extent of emotional, cognitive impairment correlate with the intensity of the pain and the duration of the condition (7). Finally, magnetic resonance studies show that chronic pain is associated with decreased gray matter density in various PFC regions (10, 11). Thus, the e...
Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy type IIC (HMSN IIC, also known as HMSN2C or Charcot-Marie-Tooth disease type 2C (CMT2C)) are phenotypically heterogeneous disorders involving topographically distinct nerves and muscles. We originally described a large New England family of French-Canadian origin with SPSMA and an American family of English and Scottish descent with CMT2C1,2. We mapped SPSMA and CMT2C risk loci to 12q24.1–q24.31 with an overlapping region between the two diseases3,4. Further analysis reduced the CMT2C risk locus to a 4-Mb region5. Here we report that SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4). Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins. Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism and possible options for therapy for these disorders.
The receptor tyrosine kinases represent an important class of signal transduction molecules that have been shown to play critical roles in neural development. We report in the present study that the neuregulin receptor ErbB4 is preferentially expressed by interneurons that are migrating tangentially from the ventral to the dorsal rat telencephalon. ErbB4 immunoreactivity was detected in the medial ganglionic eminence as early as embryonic day (E) 13 at the inception of tangential migration. Prominent ErbB4-positive migratory streams consisting of cells double-labeled with ErbB4 and Dlx, a marker of tangentially migrating cells, were found to advance along the lower intermediate zone and the marginal zone from the ventrolateral to the dorsomedial cortex at E16-E18. After E20, the ErbB4-positive stream in the lower intermediate zone shifted towards the germinal zone and further extended via the cortex into the hippocampal primordium. ErbB4 was not expressed by Tbr1-positive glutamatergic projection neurons during development. ErbB4 was preferentially expressed by the majority of parvalbumin-positive interneurons and subsets of other GABAergic interneurons in the cerebral cortex and the hippocampus in adulthood. The early onset and preferential expression of ErbB4 in tangentially migrating interneurons suggests that neuregulin/ErbB4 signaling may regulate the development and function of telencephalic interneurons.
Correlative studies have strongly linked phasic changes in dopamine activity with reward prediction error signaling. But causal evidence that these brief changes in firing actually serve as error signals to drive associative learning is more tenuous. While there is direct evidence that brief increases can substitute for positive prediction errors, there is no comparable evidence that similarly brief pauses can substitute for negative prediction errors. Lacking such evidence, the effect of increases in firing could reflect novelty or salience, variables also correlated with dopamine activity. Here we provide such evidence, showing in a modified Pavlovian over-expectation task that brief pauses in the firing of dopamine neurons in rat ventral tegmental area at the time of reward are sufficient to mimic the effects of endogenous negative prediction errors. These results support the proposal that brief changes in the firing of dopamine neurons serve as full-fledged bidirectional prediction error signals.
Background Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses. Methods To identify the METH-induced epigenetic underpinnings of these adaptations in the brain, we injected increasing METH doses to rats for two weeks and measured striatal glutamate receptor expression. We then quantified the effects of METH exposure on histone acetylation using chromatin immunoprecipitation (ChIP) and qPCR. We also measured METH-induced changes in DNA methylation and hydroxylation by using methylated (Me) and hydroxymethylated (hMe) DNA precipitation (DIP) and qPCR. Results Chronic METH decreased transcript and protein expression of GluA1 and GluA2 AMPAR and GluN1 NMDAR subunits. These changes were associated with decreased electrophysiological glutamatergic responses in striatal neurons. ChIP-PCR revealed that METH decreased enrichment of acetylated histone H4 on GluA1, GluA2, and GluN1 promoters. METH also increased protein levels of histone deacetylases (HDAC1, HDAC2 and SIRT2), protein repressors (REST and CoREST), and of the methylated DNA binding protein, MeCP2. Moreover, METH exposure increased CoREST, MeCP2, and HDAC2, but not SIRT1 or SIRT2, enrichment onto GluA1 and GluA2 gene sequences. Furthermore, METH caused interactions of CoREST and MeCP2 with HDAC2 and of REST with HDAC1. Surprisingly, MeDIP and hMeDIP-PCR revealed METH-induced decreased enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter sequences. Furthermore, the HDAC inhibitor, valproic acid, blocked METH-induced decreased expression of AMPAR and NMDAR subunits. Finally, valproic acid also attenuated METH-induced decreased H4K16Ac recruitment on AMPAR gene sequences. Conclusions These observations suggest that histone H4 hypoacetylation might be the main determinant of METH-induced decreased striatal glutamate receptor expression.
Sharp-wave associated field-oscillations (~200 Hz) of the hippocampus, referred to as “ripples”, are believed to be important for consolidation of explicit memory. Little is known about how ripples are regulated by other brain regions. Here we show that the median raphe region (MnR) plays a key role in regulating hippocampal ripple activity and memory consolidation. We performed in vivo simultaneous recording in the MnR and hippocampus, and found that when a group of MnR neurons were active, ripples were absent. Consistently, optogenetic stimulation of MnR neurons suppressed ripple activity, while inhibition of these neurons increased ripple activity. Importantly, using a fear conditioning procedure, we provided evidence that photostimulation of MnR neurons interfered with memory consolidation. Our results demonstrate a critical role of the MnR in regulating ripples and memory consolidation.
SUMMARY Imagination, defined as the ability to interpret reality in ways that diverge from past experience, is fundamental to adaptive behavior. This can be seen at a simple level in our capacity to predict novel outcomes in new situations. The ability to anticipate outcomes never before received can also influence learning if those imagined outcomes are not received. The orbitofrontal cortex is a key candidate for where the process of imagining likely outcomes occurs; however its precise role in generating these estimates and applying them to learning remain open questions. Here we address these questions by showing that single-unit activity in orbitofrontal cortex reflects novel outcome estimates. The strength of these neural correlates predicted both behavior and learning, learning which was abolished by temporally-specific inhibition of orbitofrontal neurons. These results are consistent with the proposal that the orbitofrontal cortex is critical for integrating information to imagine future outcomes.
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