Cerebellar granule cell migration and folia development require Mllt11/Af1q/Tcf7c.

The organization of neurons into distinct layers, known as lamination, is a common feature of the nervous system. This process, which arises from the direct coupling of neurogenesis and neuronal migration, plays a crucial role in the development of the cerebellum, a structure exhibiting a distinct folding cytoarchitecture with cells arranged in discrete layers. Disruptions to neuronal migration can lead to various neurodevelopmental disorders, highlighting the significance of understanding the molecular regulation of lamination. We report a role Mllt11/Af1q/Tcf7c (myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 fused gene from chromosome 1q, also known as Mllt11 transcriptional cofactor 7; henceforth referred to Mllt11) in the migration of cerebellar granule cells (GCs). We now show that Mllt11 plays a role in both the tangential and radial migration of GCs. Loss of Mllt11 led to an accumulation of GC precursors in the rhombic lip region and a reduction in the number of GCs successfully populating developing folia. Consequently, this results in smaller folia and an overall reduction in cerebellar size. Furthermore, analysis of the anchoring centers reveals disruptions in the perinatal folia cytoarchitecture, including alterations in the Bergmann glia fiber orientation and reduced infolding of the Purkinje cell plate. Lastly, we demonstrate that Mllt11 interacts with non-muscle myosin IIB (NMIIB) and Mllt11 loss-reduced NMIIB expression. We propose that the dysregulation of NMIIB underlies altered GC migratory behavior. Taken together, the findings reported herein demonstrate a role for Mllt11 in regulating neuronal migration within the developing cerebellum, which is necessary for its proper neuroanatomical organization.

Abstinence-Dependent Effects of Long-Access Cocaine Self-Administration on Nucleus Accumbens Astrocytes Are Observed in Male, But Not Female, Rats.

Accumulating evidence indicates significant consequences for astrocytes associated with drug abuse. For example, reductions in structural features and synaptic colocalization of male rat nucleus accumbens (NAc) astrocytes are observed following short-access (ShA; 2 h/d) self-administration and extinction from cocaine, methamphetamine, and heroin. However, it is unknown whether these observations extend to other rodent models of drug abuse, how enduring these effects may be, and whether similar effects are observed in female rats. Here, we assess the effects of long-access (LgA; 6 h/d) cocaine self-administration and abstinence on NAc astrocytes separately in male and female rats, employing a commonly used behavioral approach to investigate the incubation of cocaine craving. NAc astrocytes from male rats exhibit extensive (∼40%) reductions in surface area, volume, and postsynaptic colocalization 45 d but not 24 h after the last self-administration session. In contrast, no effect of self-administration and abstinence was observed in astrocytes from female rats. Moreover, no effect of LgA self-administration and abstinence was observed on NAc GLT-1 expression in female rats, an effect that has been well described in males. These results indicate striking and sexually dimorphic effects of abstinence subsequent to LgA self-administration on astrocytes. Taken together, these results indicate a pivotal role of prolonged abstinence in the effects of cocaine self-administration on NAc astrocytes, and extend a growing body of evidence regarding sex differences in the cellular consequences of drug self-administration in the brain.

The effects of nicotinamide on reinstatement to cocaine seeking in male and female Sprague Dawley rats.

RATIONALE: Interventions for psychostimulant use disorders are of significant need. Nicotinamide (NAM) is a small molecule that can oppose cellular adaptations observed following cocaine exposure in the rodent self-administration and reinstatement model of addiction. In addition, utility of NAM against symptoms of withdrawal and vulnerability to relapse to cocaine use has been suggested by case studies and anecdotal reports. However, the empirical effects of NAM on drug-seeking behaviors have not been examined. OBJECTIVE: The objective of the current study was to investigate the effects of systemic NAM administration on reinstatement to cocaine seeking, using the rat self-administration/extinction/reinstatement model of cocaine addiction. METHODS: Male and female Sprague Dawley rats were trained to self-administer i.v. cocaine or food pellets for 2 hrs per day for 12 days, followed by 14-17 days of extinction, during which i.p. NAM injections (0-120 mg/kg) were given 30 minutes prior to each extinction or reinstatement session. Rats were tested on cue-, cocaine-, or food-primed reinstatement, as well as locomotor activity. RESULTS: Chronic NAM administered throughout extinction dose dependently attenuated cue-primed reinstatement in male rats, but not female rats. In contrast, acute NAM given once prior to reinstatement had no effect on reinstatement. Chronic NAM had no effect on locomotor activity or reinstatement to food seeking. CONCLUSIONS: The specificity of NAM against cue-primed reinstatement indicates that NAM may influence responsiveness to drug-associated cues, specifically in males. Future studies will examine the mechanism(s) by which NAM may exert this effect.