Guy Mittleman

The nature and identification of quantitative trait loci: a community’s view

This white paper by eighty members of the Complex Trait Consortium presents a communitys view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

Consensus Paper: Pathological Role of the Cerebellum in Autism

There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Impairments in the acquisition, retention and selection of spatial navigation strategies after medial caudate-putamen lesions in rats

Using the Morris swimming pool test of spatial navigation, medial caudate-putamen lesions in rats produce impairments in the acquisition and retention of both place and cue tasks, and impair the selection of normal navigation strategies. Also described are some novel features of spatial navigation behaviour displayed by control animals in cue and place tasks that provide insights into the performance of the caudate-putamen rats. Analyses of the swim patterns on postacquisition probe trials, in which the target platform was removed or relocated, showed that the strategy used by the caudate-putamen lesioned rats was dependent upon the task that they were required to solve. Control rats used a place strategy and distal visual cues to identify the location of the start points, the routes from the start points to the platform, and the location of the platform on both the cue and place tasks. The caudate-putamen lesioned rats used distal visual cues and a place strategy only to acquire the place task. They solved the cue task using a taxon strategy consisting of a combination of proximal and position response cues. The results suggest that when necessary, medial caudate-putamen lesioned rats, like normal rats, can use place strategies for spatial navigation, but if an alternate, perhaps simpler, taxon solution is available they seemingly ignore place information and navigate using the simpler strategy. The deficit, which has features of a neglect rather than a loss of ability per se, suggests that medial caudate-putamen neural systems are involved in the selection of alternative strategies in spatial navigation tasks.

Enhancement of amphetamine-induced locomotor activity and dopamine release in nucleus accumbens following excitotoxic lesions of the hippocampus

This study tested the hypothesis that the hippocampus modulates dopamine-dependent function of the nucleus accumbens using behavioural and neurochemical evidence. Rats with bilateral lesions of the hippocampus induced by colchicine and kainic acid exhibited equivalent levels of spontaneous locomotor activity but a potentiation of the hyperactivity produced, dose-dependently, by D-amphetamine measured in photo-cell activity cages. The same rats subsequently received unilateral implantations of a microdialysis probe aimed at the nucleus accumbens and showed elevated levels of extracellular dopamine in response to D-amphetamine but no significant difference in basal values in comparison with sham-operated controls. The results are discussed in terms of functional interactions between the hippocampus and nucleus accumbens involving the control of mesolimbic dopamine release.

High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains

Genetic reference populations, particularly the BXD recombinant inbred (BXD RI) strains derived from C57BL/6J and DBA/2J mice, are a valuable resource for the discovery of the bio‐molecular substrates and genetic drivers responsible for trait variation and covariation. This approach can be profitably applied in the analysis of susceptibility and mechanisms of drug and alcohol use disorders for which many predisposing behaviors may predict the occurrence and manifestation of increased preference for these substances. Many of these traits are modeled by common mouse behavioral assays, facilitating the detection of patterns and sources of genetic coregulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium (TMGC) have obtained phenotype data from over 250 measures related to multiple behavioral assays across several batteries: response to, and withdrawal from cocaine, 3,4‐methylenedioxymethamphetamine; “ecstasy” (MDMA), morphine and alcohol; novelty seeking; behavioral despair and related neurological phenomena; pain sensitivity; stress sensitivity; anxiety; hyperactivity and sleep/wake cycles. All traits have been measured in both sexes in approximately 70 strains of the recently expanded panel of BXD RI strains. Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent (N = 37) BXD RI lines was performed. Primary data are publicly available for heritability, sex difference and genetic analyses using the MouseTrack database, and are also available in GeneNetwork.org for quantitative trait locus (QTL) detection and genetic analysis of gene expression. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits.

Schizophrenia and psychostimulant abuse: a review and re-analysis of clinical evidence

The authors selected articles from those published between 1975 and 1994 that specifically documented psychostimulant abuse in patients determined to be schizophrenic according to recent and relatively uniform diagnostic criteria. These articles indicated that the incidence of psychostimulant abuse in schizophrenics is 2–5 times higher than that of the general public. Additionally, unlike the decline in stimulant use seen in older adults in the general population, high rates of abuse appeared to be maintained in schizophrenics. Although the incidence of abuse in this group was high, comparisons of abuse rates generated by self-report with those obtained by urinalysis indicated that the frequency of abuse is being underestimated by 15–21%. Potential factors contributing to stimulant abuse in schizophrenics, including the disease process, and the influence of chronic neuroleptic medication, were evaluated. Results indicated that the incidence of psychostimulant abuse was neither a common property of psychiatric patients, nor exclusive to schizophrenics, but appeared to be related to chronic treatment with neuroleptic drugs. Symptom severity was generally similar in schizophrenic abusers and non-abusers, which also suggested a degree of independence from the disease process. In a majority of the studies surveyed, abuse of stimulants followed disease onset. It was also found that stimulant abuse was associated with marked increases in hospitalization in this patient group, including those known to be neuroleptic medication compliant. Possible explanations for the initiation and maintenance of psychostimulant abuse in schizophrenics are discussed in relation to clinical and preclinical evidence on drug addiction.

The Hippocampus and Reward: Effects of Hippocampal Lesions on Progressive-Ratio Responding

Two experiments investigated the effects of ibotenic-acid lesions of the hippocampus on food-rewarded performance under a progressive-ratio 10 schedule of reinforcement. The results of Experiment 1 indicated that rats with hippocampal lesions showed profound increases in breakpoint and enhancements in the efficiency of responding. In a second experiment the same rats were challenged with prefeeding, increases in the height of the response lever, and the substitution of sucrose- for grain-based reward pellets. Responding in both groups was similarly reduced by prefeeding and increases in the effortfulness of responding, but lesioned rats were significantly more responsive to the change to sucrose reward. Overall, the results indicated that hippocampal damage increased responding by enhancing the activational or hedonic properties of the delivered food pellets, while not affecting food-motivation or the motor capacity to respond.

Chronic Intermittent Injections of High-Dose Ethanol During Adolescence Produce Metabolic, Hypnotic, and Cognitive Tolerance in Rats

BACKGROUND Many humans are first exposed to ethanol during adolescence, the time at which they are most likely to binge drink ethanol. Chronic intermittent ethanol (CIE) exposure produces ethanol tolerance in adolescent rodents. Recent studies suggested that adolescent animals administered CIE experienced increased cognitive impairment following an ethanol challenge. These studies further explore development of ethanol tolerance caused by CIE in adolescence, and whether CIE during adolescence leads to altered ethanol response in adulthood. METHODS Beginning postnatal day (P) 30, adolescent rats were administered 5.0 g/kg ethanol or saline every 48 hours for 20 days. In experiment I, animals were tested for differential weight gain. In experiment II, loss of righting reflex (LORR) was observed after each injection, then at completion of pretreatment all animals were tested with 5.0 g/kg ethanol and LORR was observed. In experiment III, blood ethanol levels were observed and elimination rates calculated after the first and fifth pretreatments. All animals were tested with 5.0 g/kg at completion of pretreatment and elimination rates were recalculated. In experiment IV, animals were trained on the spatial version of the Morris Water Maze Task (MWMT) on non-treatment days. Following completion of pretreatment and training, animals were tested after receiving an ethanol (1.0, 1.5, or 2.0 g/kg), or saline. Tests for experiments II, III, and IV were repeated in the same animals following 12 ethanol-free days. RESULTS Chronic intermittent ethanol exposure during adolescence caused differential weight gain (experiment I). Adolescent rats developed tolerance to ethanol-induced LORR (experiment II) and metabolic tolerance to ethanol (experiment III). This tolerance was seen after 12 ethanol-free days. CIE also attenuated ethanol-induced spatial memory deficits in the MWMT (experiment IV). This effect was not long-lasting. CONCLUSIONS Following CIE pretreatment during adolescence, tolerance developed to the hypnotic and cognitive impairing effects of ethanol, along with increased metabolic rate and decreased weight gain. These results further emphasize the ability of CIE to produce a variety of effects during adolescence, some having long-lasting consequences.

The role of D1 and D2 receptors in the heightened locomotion induced by direct and indirect dopamine agonists in rats with hippocampal damage: An animal analogue of schizophrenia

Rats with limbic system damage display increases in responsivity to sensory stimulation and changes in the sensitivity to amphetamine, suggesting that their condition may parallel that of human schizophrenia. This experiment examined locomotion and stereotyped behavior in mature, male rats that had received aspirative lesions of the hippocampus, control lesions of the overlying parietal cortex, or were unoperated controls. Locomotion, measured as photocell beam breaks, was recorded during 2- or 3-h test sessions. Behavioral stereotypy was simultaneously rated. Hippocampal lesioned rats exhibited a selective enhancement in locomotion following D-amphetamine (0.0-5.6 mg/kg) when compared to animals in the control groups. Similar results were observed following injections of apomorphine (0.0-0.25 mg/kg), a mixed D1 and D2 agonist. In order to determine if D1 or D2 receptors were involved in this increased locomotion, the D1 agonist SKF 38393 (0.0-15 mg/kg) and the D2 agonist quinpirole (0.0-0.5 mg/kg) were tested alone and in combination. Hippocampal-ablated rats showed significantly increased locomotion only in response to quinpirole, suggesting that these lesion-induced increases were largely mediated by D2 receptors. When both drugs were administered together, SKF 38393 further enhanced the locomotor stimulating effects of quinpirole in hippocampal lesioned rats, indicating a synergistic interaction between D1 and D2 receptors in the modulation of locomotion. These findings provide further evidence of hippocampal modulation of locomotion and suggest that dopaminergic mechanisms in the nucleus accumbens, probably involving changes in receptor sensitivity, are involved. The results are discussed in relation to the functional roles of the nucleus accumbens and in terms of their implications for mental diseases including schizophrenia.

Cerebellar modulation of frontal cortex dopamine efflux in mice: relevance to autism and schizophrenia.

Cerebellar and frontal cortical pathologies have been commonly reported in schizophrenia, autism, and other developmental disorders. Whether there is a relationship between prefrontal and cerebellar pathologies is unknown. Using fixed potential amperometry, dopamine (DA) efflux evoked by cerebellar or, dentate nucleus electrical stimulation (50 Hz, 200 μA) was recorded in prefrontal cortex of urethane anesthetized lurcher (Lc/+) mice with 100% loss of cerebellar Purkinje cells and wildtype (+/+) control mice. Cerebellar stimulation with 25 and 100 pulses evoked prefrontal cortex DA efflux in +/+ mice that persisted for 12 and 25 s poststimulation, respectively. In contrast, 25 pulse cerebellar stimulation failed to evoke prefrontal cortex DA efflux in Lc/+ mice indicating a dependency on cerebellar Purkinje cell outputs. Dentate nucleus stimulation (25 pulses) evoked a comparable but briefer (baseline recovery within 7 s) increase in prefrontal cortex DA efflux compared to similar cerebellar stimulation in +/+ mice. However, in Lc/+ mice 25 pulse dentate nucleus evoked prefrontal cortex DA efflux was attenuated by 60% with baseline recovery within 4 s suggesting that dentate nucleus outputs to prefrontal cortex remain partially functional. DA reuptake blockade enhanced 100 pulse stimulation evoked prefrontal cortex responses, while serotonin or norepinephrine reuptake blockade were without effect indicating the specificity of the amperometric recordings to DA. Results provide neurochemical evidence that the cerebellum can modulate DA efflux in the prefrontal cortex. Together, these findings may explain why cerebellar and frontal cortical pathologies co‐occur, and may provide a mechanism that accounts for the diversity of symptoms common to multiple developmental disorders. Synapse 62:544–550, 2008.