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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Article
  • Peer Reviewed
International Journal of Comparative Psychology, Volume 18, Issue 1 (2005)

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.

    Cover page: A Continuum of Learning and Memory ResearchCreative Commons 'BY' version 4.0 license
    • Article
    • Peer Reviewed
    International Journal of Comparative Psychology, Volume 19, Issue 4 (2006)

    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.

      Cover page: The Effect of Context and CS Preexposure on Acquisition of the Classically Conditioned Eyeblink Response in RatsCreative Commons 'BY' version 4.0 license
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2020)
      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.
        Cover page: Genome-Wide Association Study in Two Cohorts from a Multi-generational Mouse Advanced Intercross Line Highlights the Difficulty of Replication
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2015)
        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.
          Cover page: Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity
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