Altered alcohol consumption patterns after traumatic brain injury (TBI) can lead to significant impairments in TBI recovery. Few preclinical models have been used to examine alcohol use across distinct phases of the post-injury period, leaving mechanistic questions unanswered. To address this, the aim of this study was to describe the histological and behavioral outcomes of a noncontusive closed-head TBI in the mouse, after which sensitivity to and consumption of alcohol were quantified, in addition to dopaminergic signaling markers. We hypothesized that TBI would alter alcohol consumption patterns and related signal transduction pathways that were congruent to clinical observations. After midline impact to the skull, latency to right after injury, motor deficits, traumatic axonal injury, and reactive astrogliosis were evaluated in C57BL/6J mice. Amyloid precursor protein (APP) accumulation was observed in white matter tracts at 6, 24, and 72 h post-TBI. Increased intensity of glial fibrillary acidic protein (GFAP) immunoreactivity was observed by 24 h, primarily under the impact site and in the nucleus accumbens, a striatal subregion, as early as 72 h, persisting to 7 days, after TBI. At 14 days post-TBI, when mice were tested for ethanol sensitivity after acute high-dose ethanol (4 g/kg, intraperitoneally), brain-injured mice exhibited increased sedation time compared with uninjured mice, which was accompanied by deficits in striatal dopamine-and cAMP-regulated neuronal phosphoprotein, 32 kDa (DARPP-32) phosphorylation. At 17 days post-TBI, ethanol intake was assessed using the Drinking-in-the-Dark paradigm. Intake across 7 days of consumption was significantly reduced in TBI mice compared with sham controls, paralleling the reduction in alcohol consumption observed clinically in the initial post-injury period. These data demonstrate that TBI increases sensitivity to ethanol-induced sedation and affects downstream signaling mediators of striatal dopaminergic neurotransmission while altering ethanol consumption. Examining TBI effects on ethanol responsitivity will improve our understanding of alcohol use post-TBI in humans.

Transgenic mice in which the tetracycline transactivator (tTA) is driven by the forebrain-specific calcium-calmodulindependent kinase IIa promoter (CaMKIIa-tTA mice) are used to study the molecular genetics of many behaviors. These mice can be crossed with other transgenic mice carrying a transgene of interest coupled to the tetracycline-responsive promoter element to produce mice with forebrain-specific expression of the transgene under investigation. The value of using CaMKIIa-tTA mice to study behavior, however, is dependent on the CaMKIIatTA mice themselves lacking a behavioral phenotype with respect to the behaviors being studied. Here we present data that suggest CaMKIIa-tTA mice have a behavioral phenotype distinct from that of their wildtype (WT) littermates. Most strikingly, we find that CaMKIIa-tTA mice, both those with a C57BL/6NTac genetic background (B6-tTA) and those with a 129S6B6F1/Tac hybrid genetic background (F1-tTA), exhibit decreased locomotor activity compared with WT littermates that could be misinterpreted as altered anxiety-like behavior. Despite this impairment, neither B6-tTA nor F1-tTA mice perform differently than their WT littermates in two commonly used learning and memory paradigms -Pavlovian fear conditioning and Morris water maze. Additionally, we find data regarding motor coordination and balance to be mixed: B6-tTA mice, but not F1-tTA mice, exhibit impaired performance on the accelerating rotarod and both perform as well as their WT littermates on the balance beam.

Background Fetal exposure to alcohol can have multiple deleterious effects, including learning disorders and behavioral and executive functioning abnormalities, collectively termed fetal alcohol spectrum disorders. Neonatal mice lacking both calcium/calmodulin-stimulated adenylyl cyclases (ACs) 1 and 8 demonstrate increased vulnerability to ethanol-induced neurotoxicity in the striatum compared to wild type (WT) controls. However, the developmental impact on surviving neurons is still unclear. Methods WT and AC1/8 knock-out (DKO) mice were administered one dose of ethanol (2.5g/kg) between postnatal days 5-7 (P5-7). At P30, brains were removed and processed for Golgi-Cox staining. Medium spiny neurons (MSNs) from the caudate putamen were analyzed for changes in dendritic complexity; number of branches, branch points and terminals, total and average dendritic length; spine density, and soma size. Results Ethanol significantly reduced the dendritic complexity and soma size in surviving MSNs regardless of genotype without affecting spine density. In the absence of ethanol, genetic deletion of AC1/8 reduced the dendritic complexity, number of branch points, spine density and soma size of MSNs compared to WT controls. Conclusion These data indicate that neonatal exposure to a single dose of ethanol is sufficient to cause long-term alterations in the dendritic complexity of MSNs and that this outcome is not altered by the functional status of AC1 and AC8. Therefore, although deletion of AC1/8 demonstrates a role for the adenylyl cyclases in normal morphologic development and ethanol-induced neurodegeneration, loss of AC1/8 activity does not exacerbate the effects of ethanol on dendritic morphology or spine density.