The Cerebellum and SIDS: Disordered Breathing in a Mouse Model of Developmental Cerebellar Purkinje Cell Loss during Recovery from Hypercarbia.

The cerebellum assists coordination of somatomotor, respiratory, and autonomic actions. Purkinje cell alterations or loss appear in sudden infant death and sudden death in epilepsy victims, possibly contributing to the fatal event. We evaluated breathing patterns in 12 wild-type (WT) and Lurcher mutant mice with 100% developmental cerebellar Purkinje cell loss under baseline (room air), and recovery from hypercapnia, a concern in sudden death events. Six mutant and six WT mice were exposed to 4-min blocks of increasing CO2 (2, 4, 6, and 8%), separated by 4-min recovery intervals in room air. Breath-by-breath patterns, including depth of breathing and end-expiratory pause (EEP) durations during recovery, were recorded. No baseline genotypic differences emerged. However, during recovery, EEP durations significantly lengthened in mutants, compared to WT mice, following the relatively low levels of CO2 exposure. Additionally, mutant mice exhibited signs of post-sigh disordered breathing during recovery following each exposure. Developmental cerebellar Purkinje cell loss significantly affects compensatory breathing patterns following mild CO2 exposure, possibly by inhibiting recovery from elevated CO2. These data implicate cerebellar Purkinje cells in the ability to recover from hypercarbia, suggesting that neuropathologic changes or loss of these cells contribute to inadequate ventilatory recovery to increased environmental CO2. Multiple disorders, including sudden infant death syndrome (SIDS) and sudden unexpected death in epilepsy (SUDEP), appear to involve both cardiorespiratory failure and loss or injury to cerebellar Purkinje cells; the findings support the concept that such neuropathology may precede and exert a prominent role in these fatal events.

Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel.

RATIONALE: Cocaine addiction is a major public health problem with a substantial genetic basis for which the biological mechanisms remain largely unknown. Systems genetics is a powerful method for discovering novel mechanisms underlying complex traits, and intravenous drug self-administration (IVSA) is the gold standard for assessing volitional drug use in preclinical studies. We have integrated these approaches to identify novel genes and networks underlying cocaine use in mice. METHODS: Mice from 39 BXD strains acquired cocaine IVSA (0.56 mg/kg/infusion). Mice from 29 BXD strains completed a full dose-response curve (0.032-1.8 mg/kg/infusion). We identified independent genetic correlations between cocaine IVSA and measures of environmental exploration and cocaine sensitization. We identified genome-wide significant quantitative trait loci (QTL) on chromosomes 7 and 11 associated with shifts in the dose-response curve and on chromosome 16 associated with sessions to acquire cocaine IVSA. Using publicly available gene expression data from the nucleus accumbens, midbrain, and prefrontal cortex of drug-naïve mice, we identified Aplp1 and Cyfip2 as positional candidates underlying the behavioral QTL on chromosomes 7 and 11, respectively. A genome-wide significant trans-eQTL linking Fam53b (a GWAS candidate for human cocaine dependence) on chromosome 7 to the cocaine IVSA behavioral QTL on chromosome 11 was identified in the midbrain; Fam53b and Cyfip2 were co-expressed genome-wide significantly in the midbrain. This finding indicates that cocaine IVSA studies using mice can identify genes involved in human cocaine use. CONCLUSIONS: These data provide novel candidate genes underlying cocaine IVSA in mice and suggest mechanisms driving human cocaine use.

Performance of C57BL/6J and DBA/2J mice on a touchscreen-based attentional set-shifting task.

Attentional set-shifting deficits are a feature of multiple psychiatric disorders. However, the neurogenetic mechanisms underlying these deficits are largely unknown. In the present study we assessed performance of C57BL/6J and DBA/2J mice on a touchscreen-based attentional set-shifting task similar to those used with humans and non-human primates. In experiment 1, mice discriminated simple white lines followed by compound stimuli composed of white lines superimposed on grey shapes. Although performance of the two strains was largely equivalent during early stages of the task, DBA/2J mice committed significantly more errors compared to C57BL/6J mice on the extra-dimensional shift. Additionally, performance of mice as a group declined across the three compound discrimination reversals. In experiment 2 we assessed salience of the shapes and lines dimensions and determined if dimensional salience, a variable previously shown to affect set-shifting abilities in humans and non-human primates, could be systematically manipulated. Findings from experiment 2 suggested that strain differences during the extra-dimensional shift in experiment 1 were most parsimoniously explained by a consistently impaired ability in DBA/2J mice to discriminate a subset of the compound stimuli. Additionally, unlike maze-based tasks, the relative salience of the two dimensions could be manipulated by systematically altering the width of lines exemplars while retaining other potentially-relevant attributes of the compound stimuli. These findings reveal unique and in some cases strain-dependent phenomena related to discriminations of simple and multidimensional visual stimuli which may facilitate future efforts to identify and fully characterize visual discrimination, reversal learning, and attentional set-shifting deficits in mice.

Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in males and the most common genetic cause of autism. Although executive dysfunction is consistently found in humans with FXS, evidence of executive dysfunction in Fmr1 KO mice, a mouse model of FXS, has been inconsistent. One possible explanation for this is that executive dysfunction in Fmr1 KO mice, similar to humans with FXS, is only evident when cognitive demands are high. Using touchscreen operant conditioning chambers, male Fmr1 KO mice and their male wildtype littermates were tested on the acquisition of a pairwise visual discrimination followed by four serial reversals of the response rule. We assessed reversal learning performance under two different conditions. In the first, the correct stimulus was salient and the incorrect stimulus was non-salient. In the second and more challenging condition, the incorrect stimulus was salient and the correct stimulus was non-salient; this increased cognitive load by introducing conflict between sensory-driven (i.e., bottom-up) and task-dependent (i.e., top-down) signals. Fmr1 KOs displayed two distinct impairments relative to wildtype littermates. First, Fmr1 KOs committed significantly more learning-type errors during the second reversal stage, but only under high cognitive load. Second, during the first reversal stage, Fmr1 KOs committed significantly more attempts to collect a reward during the timeout following an incorrect response. These findings indicate that Fmr1 KO mice display executive dysfunction that, in some cases, is only evident under high cognitive load.