Journal of Neuroscience Brief Communications

Cannabidiol, a Nonpsychotropic Component of Cannabis, Inhibits Cue-Induced Heroin Seeking and Normalizes Discrete Mesolimbic Neuronal Disturbances

Ren, Y., Whittard, J., Higuera-Matas, A., Morris, C. V., Hurd, Y. L. — Wed, 25 Nov 2009 10:03:10 PST

There remains debate regarding the impact of cannabis on neuropsychiatric disorders. Here, we examined the effects of cannabidiol (CBD), a nonpsychoactive constituent of cannabis, on heroin self-administration and drug-seeking behavior using an experimental rat model. CBD (5–20 mg/kg) did not alter stable intake of heroin self-administration, extinction behavior, or drug seeking induced by a heroin prime injection. Instead, it specifically attenuated heroin-seeking behavior reinstated by exposure to a conditioned stimulus cue. CBD had a protracted effect with significance evident after 24 h and even 2 weeks after administration. The behavioral effects were paralleled by neurobiological alterations in the glutamatergic and endocannabinoid systems. Discrete disturbances of AMPA GluR1 and cannabinoid type-1 receptor expression observed in the nucleus accumbens associated with stimulus cue-induced heroin seeking were normalized by CBD treatment. The findings highlight the unique contributions of distinct cannabis constituents to addiction vulnerability and suggest that CBD may be a potential treatment for heroin craving and relapse.

Fornix Microstructure Correlates with Recollection But Not Familiarity Memory

Wed, 25 Nov 2009 10:03:10 PST

The fornix is the main tract between the medial temporal lobe (MTL) and medial diencephalon, both of which are critical for episodic memory. The precise involvement of the fornix in memory, however, has been difficult to ascertain since damage to this tract in human amnesics is invariably accompanied by atrophy to surrounding structures. We used diffusion-weighted imaging to investigate whether individual differences in fornix white matter microstructure in neurologically healthy participants were related to differences in memory as assessed by two recognition tasks. Higher microstructural integrity in the fornix tail was found to be associated with significantly better recollection memory. In contrast, there was no significant correlation between fornix microstructure and familiarity memory or performance on two non-mnemonic tasks. Our findings support the idea that there are distinct MTL–diencephalon pathways that subserve differing memory processes.

Dissociating Response Conflict and Error Likelihood in Anterior Cingulate Cortex

Yeung, N., Nieuwenhuis, S. — Wed, 18 Nov 2009 10:02:12 PST

Neuroimaging studies consistently report activity in anterior cingulate cortex (ACC) in conditions of high cognitive demand, leading to the view that ACC plays a crucial role in the control of cognitive processes. According to one prominent theory, the sensitivity of ACC to task difficulty reflects its role in monitoring for the occurrence of competition, or "conflict," between responses to signal the need for increased cognitive control. However, a contrasting theory proposes that ACC is the recipient rather than source of monitoring signals, and that ACC activity observed in relation to task demand reflects the role of this region in learning about the likelihood of errors. Response conflict and error likelihood are typically confounded, making the theories difficult to distinguish empirically. The present research therefore used detailed computational simulations to derive contrasting predictions regarding ACC activity and error rate as a function of response speed. The simulations demonstrated a clear dissociation between conflict and error likelihood: fast response trials are associated with low conflict but high error likelihood, whereas slow response trials show the opposite pattern. Using the N2 component as an index of ACC activity, an EEG study demonstrated that when conflict and error likelihood are dissociated in this way, ACC activity tracks conflict and is negatively correlated with error likelihood. These findings support the conflict-monitoring theory and suggest that, in speeded decision tasks, ACC activity reflects current task demands rather than the retrospective coding of past performance.

Overexpression of the Wild-Type SPT1 Subunit Lowers Desoxysphingolipid Levels and Rescues the Phenotype of HSAN1

Wed, 18 Nov 2009 10:02:13 PST

Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT) cause an adult-onset, hereditary sensory, and autonomic neuropathy type I (HSAN1). We previously reported that mice bearing a transgene-expressing mutant SPTLC1 (tgSPTLC1^C133W) show a reduction in SPT activity and hyperpathia at 10 months of age. Now analyzed at a later age, we find these mice develop sensory loss with a distal small fiber neuropathy and peripheral myelinopathy. This phenotype is largely reversed when these mice are crossed with transgenic mice overexpressing wild-type SPTLC1 showing that the mutant SPTLC1 protein is not inherently toxic. Simple loss of SPT activity also cannot account for the HSAN1 phenotype, since heterozygous SPTLC1 knock-out mice have reduced SPT activity but are otherwise normal. Rather, the presence of two newly identified, potentially deleterious deoxysphingoid bases in the tgSPTLC1^C133W, but not in the wild-type, double-transgenic tgSPTLC1^{WT + C133W} or SPTLC1^+/– mice, suggests that the HSAN1 mutations alter amino acid selectivity of the SPT enzyme such that palmitate is condensed with alanine and glycine, in addition to serine. This observation is consistent with the hypothesis that HSAN1 is the result of a gain-of-function mutation in SPTLC1 that leads to accumulation of a toxic metabolite.

Endogenous Rhythms in Period1 Mutant Suprachiasmatic Nuclei In Vitro Do Not Represent Circadian Behavior

Pendergast, J. S., Friday, R. C., Yamazaki, S. — Wed, 18 Nov 2009 10:02:13 PST

The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) controls daily rhythms of behavior and physiology. Lesions of the SCN cause arrhythmicity of locomotor activity, and transplants of fetal SCN tissue restore rhythmic behavior that is consistent with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. While several studies have demonstrated that the circadian characteristics of in vitro SCN rhythms represent circadian behavior, others have shown that the periods of explanted SCN are not always congruent with locomotor activity. We find that the aberrant rhythms of ex vivo SCN lacking functional Period1 (Per1^–/–) do not represent the behavioral rhythms of the mutant animals. Surprisingly, in C57BL/6J Per1^–/– mice, the real-time circadian gene promoter activity rhythm is weak or absent in adult SCN slices in vitro even though the free-running wheel-running activity rhythm is indistinguishable from wild-type (Per1^+/+) mice. While some neurons in Per1^–/– SCN explants exhibit robust circadian rhythms, others have irregular and/or low-amplitude rhythms. Together, these data suggest that either a small population of rhythmic neurons in the Per1^–/– SCN is sufficient to control wheel-running activity or that in vivo physiological factors can compensate for the aberrant endogenous rhythms of Per1^–/– SCN.

A Novel, Nongenomic Mechanism Underlies Retinoic Acid-Induced Growth Cone Turning

Farrar, N. R., Dmetrichuk, J. M., Carlone, R. L., Spencer, G. E. — Wed, 11 Nov 2009 10:02:14 PST

The vitamin A metabolite, retinoic acid (RA), is well known for its roles in neural development and regeneration. We have previously shown that RA can induce positive growth cone turning in regenerating neurons in vitro. In this study, we address the subcellular mechanisms underlying this chemo-attractive response, using identified central neurons from the adult mollusc, Lymnaea stagnalis. We show that the RA-induced positive growth cone turning was maintained in the presence of the transcriptional inhibitor, actinomycin D. We also physically transected the neurites from the cell body and showed that isolated growth cones retain the capacity to turn toward a gradient of RA. Moreover, this attractive turning is dependent on de novo local protein synthesis and Ca²⁺ influx. Most of RA's actions during neurite outgrowth and regeneration require gene transcription, although these data show for the first time in any species, that the chemotropic action of RA in guiding neurite outgrowth, involves a novel, nongenomic mechanism.

Why Sex Matters: Brain Size Independent Differences in Gray Matter Distributions between Men and Women

Luders, E., Gaser, C., Narr, K. L., Toga, A. W. — Wed, 11 Nov 2009 10:02:14 PST

The different brain anatomy of men and women is both a classic and continuing topic of major interest. Among the most replicated and robust sex differences are larger overall brain dimensions in men, and relative increases of global and regional gray matter (GM) in women. However, the question remains whether sex-typical differences in brain size (i.e., larger male and smaller female brains) or biological sex itself account for the observed sex effects on tissue amount and distribution. Exploring cerebral structures in men and women with similar brain size may clarify the true contribution of biological sex. We thus examined a sample of 24 male and 24 female subjects with brains identical in size, in addition to 24 male and 24 female subjects with considerable brain size differences. Using this large set of brains (n = 96), we applied a well validated and automated voxel-based approach to examine regional volumes of GM. While we revealed significant main effects of sex, there were no significant effects of brain size (and no significant interactions between sex and brain size). When conducting post hoc tests, we revealed a number of regions where women had larger GM volumes than men. Importantly, these sex effects remained evident when comparing men and women with the same brain size. Altogether, our findings suggest that the observed increased regional GM volumes in female brains constitute sex-dependent redistributions of tissue volume, rather than individual adjustments attributable to brain size.

Brain Gray Matter Decrease in Chronic Pain Is the Consequence and Not the Cause of Pain

Rodriguez-Raecke, R., Niemeier, A., Ihle, K., Ruether, W., May, A. — Wed, 04 Nov 2009 10:02:51 PST

Recently, local morphologic alterations of the brain in areas ascribable to the transmission of pain were reported in patients suffering from chronic pain. Although some authors discussed these findings as damage or loss of brain gray matter, one of the key questions is whether these structural alterations in the cerebral pain-transmitting network precede or succeed the chronicity of pain. We investigated 32 patients with chronic pain due to primary hip osteoarthritis and found a characteristic gray matter decrease in patients compared with controls in the anterior cingulate cortex (ACC), right insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC), amygdala, and brainstem. We then investigated a subgroup of these patients (n = 10) 6 weeks and 4 months after total hip replacement surgery, monitoring whole brain structure. After surgery, all 10 patients were completely pain free and we observed a gray matter increase in the DLPFC, ACC, amygdala, and brainstem. As gray matter decrease is at least partly reversible when pain is successfully treated, we suggest that the gray matter abnormalities found in chronic pain do not reflect brain damage but rather are a reversible consequence of chronic nociceptive transmission, which normalizes when the pain is adequately treated.