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There has been extensive discussion of the "Replication Crisis" in many fields, including genome-wide association studies (GWAS). We explored replication in a mouse model using an advanced intercross line (AIL), which is a multigenerational intercross between two inbred strains. We re-genotyped a previously published cohort of LG/J x SM/J AIL mice (F34; n = 428) using a denser marker set and genotyped a new cohort of AIL mice (F39-43; n = 600) for the first time. We identified 36 novel genome-wide significant loci in the F34 and 25 novel loci in the F39-43 cohort. The subset of traits that were measured in both cohorts (locomotor activity, body weight, and coat color) showed high genetic correlations, although the SNP heritabilities were slightly lower in the F39-43 cohort. For this subset of traits, we attempted to replicate loci identified in either F34 or F39-43 in the other cohort. Coat color was robustly replicated; locomotor activity and body weight were only partially replicated, which was inconsistent with our power simulations. We used a random effects model to show that the partial replications could not be explained by Winner's Curse but could be explained by study-specific heterogeneity. Despite this heterogeneity, we performed a mega-analysis by combining F34 and F39-43 cohorts (n = 1,028), which identified four novel loci associated with locomotor activity and body weight. These results illustrate that even with the high degree of genetic and environmental control possible in our experimental system, replication was hindered by study-specific heterogeneity, which has broad implications for ongoing concerns about reproducibility.

There has been extensive discussion of the "Replication Crisis" in many fields, including genome-wide association studies (GWAS). We explored replication in a mouse model using an advanced intercross line (AIL), which is a multigenerational intercross between two inbred strains. We re-genotyped a previously published cohort of LG/J x SM/J AIL mice (F34; n = 428) using a denser marker set and genotyped a new cohort of AIL mice (F39-43; n = 600) for the first time. We identified 36 novel genome-wide significant loci in the F34 and 25 novel loci in the F39-43 cohort. The subset of traits that were measured in both cohorts (locomotor activity, body weight, and coat color) showed high genetic correlations, although the SNP heritabilities were slightly lower in the F39-43 cohort. For this subset of traits, we attempted to replicate loci identified in either F34 or F39-43 in the other cohort. Coat color was robustly replicated; locomotor activity and body weight were only partially replicated, which was inconsistent with our power simulations. We used a random effects model to show that the partial replications could not be explained by Winner's Curse but could be explained by study-specific heterogeneity. Despite this heterogeneity, we performed a mega-analysis by combining F34 and F39-43 cohorts (n = 1,028), which identified four novel loci associated with locomotor activity and body weight. These results illustrate that even with the high degree of genetic and environmental control possible in our experimental system, replication was hindered by study-specific heterogeneity, which has broad implications for ongoing concerns about reproducibility.

Psychostimulant addiction is a heritable substance use disorder; however its genetic basis is almost entirely unknown. Quantitative trait locus (QTL) mapping in mice offers a complementary approach to human genome-wide association studies and can facilitate environment control, statistical power, novel gene discovery, and neurobiological mechanisms. We used interval-specific congenic mouse lines carrying various segments of chromosome 11 from the DBA/2J strain on an isogenic C57BL/6J background to positionally clone a 206 kb QTL (50,185,512-50,391,845 bp) that was causally associated with a reduction in the locomotor stimulant response to methamphetamine (2 mg/kg, i.p.; DBA/2J < C57BL/6J)-a non-contingent, drug-induced behavior that is associated with stimulation of the dopaminergic reward circuitry. This chromosomal region contained only two protein coding genes-heterogeneous nuclear ribonucleoprotein, H1 (Hnrnph1) and RUN and FYVE domain-containing 1 (Rufy1). Transcriptome analysis via mRNA sequencing in the striatum implicated a neurobiological mechanism involving a reduction in mesolimbic innervation and striatal neurotransmission. For instance, Nr4a2 (nuclear receptor subfamily 4, group A, member 2), a transcription factor crucial for midbrain dopaminergic neuron development, exhibited a 2.1-fold decrease in expression (DBA/2J < C57BL/6J; p 4.2 x 10-15). Transcription activator-like effector nucleases (TALENs)-mediated introduction of frameshift deletions in the first coding exon of Hnrnph1, but not Rufy1, recapitulated the reduced methamphetamine behavioral response, thus identifying Hnrnph1 as a quantitative trait gene for methamphetamine sensitivity. These results define a novel contribution of Hnrnph1 to neurobehavioral dysfunction associated with dopaminergic neurotransmission. These findings could have implications for understanding the genetic basis of methamphetamine addiction in humans and the development of novel therapeutics for prevention and treatment of substance abuse and possibly other psychiatric disorders.

Animals must distinguish the sensory consequences of self-generated movements (reafference) from those of other-generated movements (exafference). Only self-generated movements entail the production of motor copies (i.e., corollary discharges), which are compared with reafference in the cerebellum to compute predictive or internal models of movement. Internal models emerge gradually over the first three postnatal weeks in rats through a process that is not yet fully understood. Previously, we demonstrated in postnatal day (P) 8 and P12 rats that precerebellar nuclei convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce limb twitches. Here, recording from a deep cerebellar nucleus (interpositus, IP) in P12 rats of both sexes, we compared reafferent and exafferent responses with twitches and limb stimulations, respectively. As expected, most IP units showed robust responses to twitches. However, in contrast with other sensory structures throughout the brain, relatively few IP units showed exafferent responses. Upon finding that exafferent responses occurred in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimicked the effects of urethane on exafference. Finally, the results suggest that twitch-related corollary discharge and reafference are conveyed simultaneously and in parallel to cerebellar cortex and IP. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized corollary discharge and reafference, thereby enabling the development of closed-loop circuits and, subsequently, internal models. [ABSTRACT FROM AUTHOR]

In a previous study, a latent inhibition (LI) effect was found to be dictated by a facilitation of the acquisition of a conditioned eyeblink response in context pre-exposed rabbits as opposed to slower learning in tone preexposed rabbits. In the present experiments, we examined the effects of preexposure to the tone conditional stimulus (CS) using a similar paradigm with rats. In Experiment 1, rats were given four or eight days of context (SIT) or CS preexposure (TONE) followed by eight days of paired training. Unlike rabbits, control and eight day SIT groups learned faster than TONE exposed rats and the four day SIT group. In Experiment 2, we controlled for the context preexposure control rats received during adaptation in Experiment 1 and tested rats given two days of CS preexposure or no preexposure. Again, SIT rats learned faster than TONE rats as well as rats that did not receive any preexposure. In Experiment 3, we tested a frequently-used method for examining LI, whereby paired training began immediately after the last of four sessions of preexposure, but observed no effect. Similar to our previous results, any LI effect produced in the present set of experiments arose from facilitated performance by SIT rats as opposed to deficits in learning in TONE rats. The present results highlight the need for a unifying theory of preexposure effects immune to differences experimental paradigms and parameters in order explain the variety of results obtained in the field.

History has revealed time and time again that science is moved forward by revolutions that pit one point of view, theory, or methodology, against an opposing view. During calmer times, however, we as researchers are left to our own devices and settle into our work with little thought to the world around us. The field of learning and memory has been privy to many such revolutions in the past but has yet to form a cohesive, modern message. Grau and Joynes suggest that our strong ties to the past are to blame for a lack of progression in the field. We agree and add that the focus of the field on two extreme ends of a continuum has also held us back; suggesting that research that goes on in the middle of the continuum may be the key to leading the field out of its rut.

Glyoxalase 1 (Glo1) expression has previously been associated with anxiety in mice; however, its role in anxiety is controversial, and the underlying mechanism is unknown. Here, we demonstrate that GLO1 increases anxiety by reducing levels of methylglyoxal (MG), a [GABA.sub.A] receptor agonist. Mice overexpressing Glo1 on a Tg bacterial artificial chromosome displayed increased anxiety-like behavior and reduced brain MG concentrations. Treatment with low doses of MG reduced anxiety-like behavior, while higher doses caused locomotor depression, ataxia, and hypothermia, which are characteristic effects of [GABA.sub.A] receptor activation. Consistent with these data, we found that physiological concentrations of MG selectively activated [GABA.sub.A] receptors in primary neurons. These data indicate that GLO1 increases anxiety by reducing levels of MG, thereby decreasing [GABA.sub.A] receptor activation. More broadly, our findings potentially link metabolic state, neuronal inhibitory tone, and behavior. Finally, we demonstrated that pharmacological inhibition of GLO1 reduced anxiety, suggesting that GLO1 is a possible target for the treatment of anxiety disorders., Introduction Anxiety disorders, such as post-traumatic stress disorder, panic disorder, social phobia, specific phobia, and generalized anxiety disorder, comprise the most common psychiatric diseases in the United States (1). Mouse [...]

In the authors' original article (M. S. Blumberg & G. Sokoloff, 2001), they provided evidence that the ultrasonic vocalizations of infant rats are acoustic by-products of a physiological maneuver. In J. Panksepp's (2003) comment, he sidestepped the authors' empirical findings and focused on his concern that their perspective might prevent progress toward his ultimate goal of understanding the neural substrates of emotion in mammals. In this reply, the authors question the reliability of J. Panksepp's strategy for studying emotion on the basis that anthropomorphism has yet to prove itself an effective research tool. In addition, the authors believe that J. Panksepp's anthropomorphic-zoomorphic strategy defeats the goal of building a comparative psychobiology of behavior and cognition that does not reify false distinctions between humans and other animals.

Infant Syrian golden hamsters (Mesocricetus auratus) do not exhibit endogenous heat production before 3 weeks of age and do not huddle effectively during cold exposure, gaining little thermoregulatory benefit from the presence of multiple littermates. In contrast, infant Norway rats (Rattus norvegicus) produce heat endogenously and are effective at maintaining elevated body temperatures by huddling. Therefore, the ineffective huddling of infant hamsters may be due to the absence of endogenous heat production. The huddling behavior of infants in mixed huddles of 8-day-old hamsters and weight-matched 4-5-day-old rats was observed to explore this possibility. The results indicate that hamsters, even when cold, effectively gain access to heat-producing rats, supporting the idea that endothermy contributes to the behavior of huddling by providing heat to each individual and thermal stimuli to other infants to support aggregation.

The responses of 2- and 8-day-old rats (Rattus norvegicus) and hamsters (Mesocricetus auratus) to thermal stimulation were assessed in 4 experiments. In Experiment 1, the surface underlying the pup was cooled, and the latency to escape to a region of warmth was measured. Experiment 2 required pups to locomote farther to gain access to warmth. Experiment 3 was similar to Experiment 1 except the underlying surface was heated. Finally, in Experiment 4, locomotor behavior was assessed during isothermal cooling in which there was no possibility for escape. In general, hamsters exhibited more rapid and robust responses to thermal stimulation than rats. A framework for interpreting these results is presented emphasizing how differences in locomotor and thermogenic capabilities influence thermoregulatory behavior under different task conditions.

Two experiments were conducted to investigate if thermogenesis from brown adipose tissue (BAT) modulates cardiac activity in infant rats. During the experiments, a ganglionic blocker was injected to remove the influence from other factors that can alter the heart rate before the administration of a beta3 adrenoreceptor agonist, a BAT thermogenesis activator. The results of the experiments suggest that BAT thermogenesis maintains heart rate during cold exposure.

The interaction between brown adipose tissue (BAT) thermogenic function and modulation of cardiac rate were analyzed in infant rats during exposure to moderate and extreme cold challenge. Analysis of rat cardiac function during cold challenge indicated the relationship between the autonomic regulation of BAT thermogenesis and maintenance of cardiac rate. Furthermore, infant rats exposed to cold challenge exhibited elevated BAT thermogenesis.