Environmental interventions reduced repetitive behavior in a mouse model.

Repetitive motor behaviors are associated with several neurodevelopmental disorders including autism spectrum disorder. Non-invasive environmental interventions that can ameliorate repetitive behavior and be introduced in early development could benefit many. In Experiment 1, we characterized the development of repetitive circling in mice reared in standard and enriched environments. Environmental enrichment was associated with reduced repetitive behavior. In Experiment 2, two weekly injections of an A2A adenosine receptor agonist reduced repetitive behavior in mice fed a ketogenic diet. Together, these two approaches modified the environment and reduced repetitive behavior with potential implications for increased functioning of the indirect basal ganglia pathway.

Benefits of a ketogenic diet on repetitive motor behavior in mice.

Repetitive motor behaviors are repetitive and invariant movements with no apparent function, and are common in several neurological and neurodevelopmental disorders, including autism spectrum disorders (ASD). However, the neuropathology associated with the expression of these abnormal stereotypic movements is not well understood, and effective treatments are lacking. The ketogenic diet (KD) has been used for almost a century to treat intractable epilepsy and, more recently, disorders associated with inflexibility of behavioral routines. Here, we show a novel application for KD to reduce an abnormal repetitive circling behavior in a rodent model. We then explore potential mediation through the striatum, as dysregulation of cortico-basal ganglia circuitry has previously been implicated in repetitive motor behavior. In Experiments 1 and 2, adult FVB mice were assessed for levels of repetitive circling across a 3-week baseline period. Mice were then switched to KD and repetitive circling was assessed for an additional 3 weeks. In Experiment 1, time on KD was associated with reduced repetitive behavior. In Experiment 2, we replicated these benefits of KD and assessed dendritic spine density in the striatum as one potential mechanism for reducing repetitive behavior, which yielded no differences. In Experiment 3, adult female circling mice were given a single administration of a dopamine D2 receptor antagonist (L-741,646) that was associated with reduced repetitive behavior over time. Future research will explore the relationship between KD and dopamine within basal ganglia nuclei that may be influencing the benefits of KD on repetitive behavior.

Childhood trauma and post-trauma environment affect fear memory and alcohol use differently in male and female mice.

BACKGROUND: Childhood trauma is associated with the development of adult mental health and substance use disorders, with females generally being more at risk. Alcohol is commonly used for coping with trauma, and alcohol use disorder (AUD) affects ∼14.4 million adult Americans annually. Research investigating sex differences in the environmental modification of anxiety and alcohol use following childhood trauma will extend our understanding of the etiology of AUD. Here, we sought to model the interacting effects of a single-episode late childhood trauma with post-trauma environment on adult alcohol use using male and female mice. METHODS: C57Bl6/J mice (d22) exposed to predator odor (TMT) or water were reared in standard environments (SE) or environmental enrichment (EE). Mice were assessed for adolescent anxiety and conditioned fear, and for adult alcohol use in a limited access, response non-contingent, alcohol exposure paradigm. RESULTS: A single exposure to predator odor was an effective stressor, inducing long-term sex-dependent changes in conditioned fear and alcohol behaviors that interacted with post-trauma environment. Adolescent EE females showed more conditioned freezing to the trauma-associated context. Adult EE mice consumed less total alcohol than SE mice. However, alcohol use across time differed for males and females. Exposure to a childhood stressor increased alcohol use significantly in females, but not males. EE males, but not EE females, drank less than SE counterparts. CONCLUSIONS: Findings from this model recapitulate greater vulnerability to childhood trauma in females and support sex differences in post-trauma development of conditioned fear and alcohol use that are modified by environment.

Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cue-induced cocaine seeking.

Ceftriaxone is an antibiotic that reliably attenuates the reinstatement of cocaine seeking after extinction while preventing the nucleus accumbens (NA) core glutamate efflux that drives reinstatement. However, when rats undergo abstinence without extinction, ceftriaxone attenuates context-primed cocaine seeking but NA core glutamate efflux still increases. Here, we sought to determine if the same would occur when cocaine seeking is prompted by both context and discrete cues (cue-induced seeking) after cocaine abstinence. Male rats self-administered intravenous cocaine accompanied by drug-associated cues (light + tone) for 2 h/day for 14 days. Rats then experienced abstinence with daily handling but no extinction training for 2 weeks. Ceftriaxone (200 mg/kg IP) or vehicle was administered during the last 6 days of abstinence. During a cue-induced cocaine seeking test, microdialysis procedures were conducted. Rats were perfused at the end of the test for later Fos analysis. A separate cohort of rats was infused with the retrograde tracer cholera toxin B in the NA core and underwent the same self-administration and relapse procedures. Ceftriaxone increased baseline glutamate and attenuated both cue-induced cocaine seeking and NA core glutamate efflux during this test. Ceftriaxone reduced Fos expression in regions sending projections to the NA core (prefrontal cortex, basolateral amygdala, ventral tegmental area) and specifically reduced Fos in prelimbic cortex and not infralimbic cortex neurons projecting to the NA core. Thus, when cocaine seeking is induced by drug-associated cues, ceftriaxone is able to attenuate relapse by preventing NA core glutamate efflux, likely through reducing activity in prelimbic NA core-projecting neurons.

Ceftriaxone and mGlu2/3 interactions in the nucleus accumbens core affect the reinstatement of cocaine-seeking in male and female rats.

RATIONALE: The beta-lactam antibiotic ceftriaxone reliably attenuates the reinstatement of cocaine seeking. While the restoration of nucleus accumbens core (NA core) GLT-1 expression is necessary for ceftriaxone to attenuate reinstatement, AAV-mediated GLT-1 overexpression is not sufficient to attenuate reinstatement and does not prevent glutamate efflux during reinstatement. AIMS: Here, we test the hypothesis that ceftriaxone attenuates reinstatement through interactions with glutamate autoreceptors mGlu2 and mGlu3 in the NA core. METHODS: Male and female rats self-administered cocaine for 12 days followed by 2-3 weeks of extinction training. During the last 6-10 days of extinction, rats received ceftriaxone (200 mg/kg IP) or vehicle. In experiment 1, rats were killed, and NA core tissue was biotinylated for assessment of total and surface expression of mGlu2 and mGlu3 via western blotting. In experiment 2, we tested the hypothesis that mGlu2/3 signaling is necessary for ceftriaxone to attenuate cue- and cocaine-primed reinstatement by administering bilateral intra-NA core infusion of mGlu2/3 antagonist LY341495 or vehicle immediately prior to reinstatement testing. RESULTS: mGlu2 expression was reduced by cocaine and restored by ceftriaxone. There were no effects of cocaine or ceftriaxone on mGlu3 expression. We observed no effects of estrus on expression of either protein. The antagonism of mGlu2/3 in the NA core during both cue- and cocaine-primed reinstatement tests prevented ceftriaxone from attenuating reinstatement. CONCLUSIONS: These results indicate that ceftriaxone's effects depend on mGlu2/3 function and possibly mGlu2 receptor expression. Future work will test this hypothesis by manipulating mGlu2 expression in pathways that project to the NA core.

The Divergent Effects of CDPPB and Cannabidiol on Fear Extinction and Anxiety in a Predator Scent Stress Model of PTSD in Rats.

Post-traumatic stress disorder (PTSD) currently has no FDA-approved treatments that reduce symptoms in the majority of patients. The ability to extinguish fear memory associations is impaired in PTSD individuals. As such, the development of extinction-enhancing pharmacological agents to be used in combination with exposure therapies may benefit the treatment of PTSD. Both mGlu5 and CB1 receptors have been implicated in contextual fear extinction. Thus, here we tested the ability of the mGlu5 positive allosteric modulator 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and cannabidiol (CBD) to reduce both conditioned and unconditioned fear. We used a predator-threat animal model of PTSD which we and others have previously shown to capture the heterogeneity of anxiety responses observed in humans exposed to trauma. Here, 1 week following a 10-min exposure to predator scent stress, rats were classified into stress-Susceptible and stress-Resilient phenotypes using behavioral criteria for elevated plus maze and acoustic startle response performance. Two weeks after classification, rats underwent 3 days of contextual fear extinction and were treated with vehicle, CDPPB or CBD prior to each session. Finally, the light-dark box test was employed to assess phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety. CDPBB but not CBD, reduced freezing in Susceptible rats relative to vehicle. In the light-dark box test for unconditioned anxiety, CBD, but not CDPPB, reduced anxiety in Susceptible rats. Resilient rats displayed reduced anxiety in the light-dark box relative to Susceptible rats. Taken together, the present data indicate that enhancement of mGlu5 receptor signaling in populations vulnerable to stress may serve to offset a resistance to fear memory extinction without producing anxiogenic effects. Furthermore, in a susceptible population, CBD attenuates unconditioned but not conditioned fear. Taken together, these findings support the use of predator-threat stress exposure in combination with stress-susceptibility phenotype classification as a model for examining the unique drug response profiles and altered neuronal function that emerge as a consequence of the heterogeneity of psychophysiological response to stress.

The effects of Pavlovian cue extinction and ceftriaxone on cocaine relapse after abstinence.

BACKGROUND: Cocaine use disorder is a significant public health problem and currently no medications are FDA-approved to reduce cocaine relapse. Drug-associated cues are reported to elicit craving and cocaine-seeking in humans. Repeated, non-reinforced presentations of drug-associated cues (cue extinction) have been proposed to reduce the ability of such cues to prompt drug-seeking. In rodent models of cocaine relapse, cue extinction reduces cocaine relapse when such extinction occurs in the same context as cocaine self-administration, which is not akin to the manner in which treatment would occur in humans. Here we sought to determine whether cue extinction outside of the cocaine self-administration context would reduce relapse in the drug context. We also hypothesized that ceftriaxone, an antibiotic consistently shown to attenuate cocaine relapse in rats, would enhance the relapse-preventing effects of cue extinction. METHODS: Rats self-administered intravenous cocaine for 12 days followed by 20-21 days of abstinence. Immediately preceding the relapse test, rats either underwent 6 single daily cue extinction sessions (1 h/day) outside the self-administration context or no extinction with daily handling. Rats also received vehicle or ceftriaxone (200 mg/kg IP) on those six days. RESULTS: Ceftriaxone attenuated cued relapse relative to vehicle-treated rats, but there was no additive effect of cue extinction on cocaine-seeking. Cue extinction alone did not attenuate relapse. CONCLUSIONS: Thus, in agreement with work in humans, when cue extinction is conducted outside the drug-associated context it does not reduce the risk of relapse alone. Ceftriaxone remains a strong possibility for medication to reduce cocaine relapse in humans.

The effects of clavulanic acid and amoxicillin on cue-primed reinstatement of cocaine seeking.

Research using the cocaine self-administration and reinstatement animal model of relapse finds that the beta-lactam antibiotic, ceftriaxone, attenuates cocaine-primed reinstatement of cocaine seeking and upregulates two proteins that regulate glutamate release and reuptake (xCT and GLT-1, respectively) in the nucleus accumbens core (NAc). We tested three compounds with beta-lactam rings for their ability to attenuate cue-primed reinstatement and increase GLT-1 and xCT expression in the NAc and prefrontal cortex (PFC). Rats self-administered intravenous cocaine for 1 hr/day for 7 days then 6 hrs/day for 10 days. Cue-primed reinstatement tests began after 8-9 days of extinction training. Rats received oral vehicle, clavulanic acid (CA), amoxicillin (AMX), or CA + AMX (Augmentin; AUG) for 5 days prior to testing. Only AMX-treated rats demonstrated a reduction of cocaine-seeking that trended toward significance, warranting future investigation of a wider range of doses. In the NAc, GLT-1a expression was reduced in vehicle-treated rats relative to cocaine-naïve controls and was not restored by AMX or AUG. CA-treated rats reinstated more than vehicle-treated rats and exhibited GLT-1a and xCT expression intermediate between cocaine-naïve controls and vehicle-treated cocaine rats. In agreement with our previous work, cocaine did not decrease PFC GLT-1a expression. Cocaine reduced xCT expression in the PFC that was unchanged by any of the three compounds. These results indicate that AMX may be another beta-lactam that attenuates cocaine relapse. Furthermore, the upregulation of both GLT-1 and xCT in the NAc may be needed to attenuate cocaine seeking. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Impairments in reversal learning following short access to cocaine self-administration.

BACKGROUND: Cocaine use disorder is characterized by compulsive drug-seeking that persists long into abstinence. Work using rodent models of cocaine addiction has found evidence for reversal learning deficits 21 days after non-contingent cocaine administration and 60 days after self-administration. Here we sought to determine if a deficit in reversal learning is present 3-4 weeks after cessation of cocaine self-administration, when relapse to cocaine-seeking is robust. Conversely, we hypothesized that reversal learning training would protect against relapse, similar to other forms of environmental enrichment. METHODS: Male rats underwent short access (ShA, 2 h/10d) or long access (LgA, 1 h/7d then 6 h/10d) cocaine self-administration, followed by 21-29 days of abstinence. During abstinence, a subset of rats underwent training in a plus-maze that required an egocentric strategy to earn a sucrose reward. Following response acquisition and retention, the ability to reverse the spatial navigation strategy was tested. RESULTS: Total trials to criteria and total errors made did not differ between the groups during response acquisition, retention, or reversal. On the first reversal test, ShA rats performed better than LgA and control rats. ShA rats' performance worsened over time. There were no effects of cognitive training or length of cocaine access on context-primed relapse of cocaine-seeking. CONCLUSIONS: The present data indicate that perhaps LgA cocaine self-administration does not produce adaptations to regions mediating context-primed relapse as it does for cocaine and cocaine-associated cue-induced reinstatement of drug-seeking. A time-dependent deficit in reversal learning was found only in ShA rats. Reversal learning training did not protect against cocaine relapse.

The effects of ceftriaxone on cue-primed reinstatement of cocaine-seeking in male and female rats: estrous cycle effects on behavior and protein expression in the nucleus accumbens.

RATIONALE: Effective pharmacological treatments to prevent cocaine relapse remain elusive. In male rats, ceftriaxone attenuates the reinstatement of cocaine-seeking while increasing glutamate transporter-1 (GLT-1) and xCT expression in the nucleus accumbens core (NAc). Despite reported sex differences in cocaine relapse, these effects have not yet been confirmed in female rats. OBJECTIVE: We investigated the effects of ceftriaxone on cue-primed reinstatement and cocaine-induced alterations in glutamatergic proteins in the NAc of female rats. Potential interactions between estrous phase and treatment were also assessed. METHOD: Male and female rats self-administered cocaine in the presence of discrete cues for 12 days, followed by 2-3 weeks of extinction. Ceftriaxone or vehicle was administered daily for a minimum of 6 days immediately preceding a cue-primed reinstatement test. RESULTS: Total cocaine intake was greater in females than in males, but reinstatement behavior was similar. Ceftriaxone attenuated reinstatement in both sexes and was accompanied by increased expression of GLT-1a and xCT in the NAc. However, ceftriaxone attenuated reinstatement only when females were tested during met-, di-, and proestrus phases and not during estrus. A significant increase in AMPA receptor subunit GluA1 surface expression was also observed during estrus, potentially influencing reinstatement. CONCLUSION: These findings extend the beneficial effects of ceftriaxone on persistent cocaine-seeking from males to females, increasing its potential as a pharmacological treatment for preventing relapse. The effects of estrus on GluA1 expression and reinstatement observed here indicate that females may need additional interventions during some phases of the menstrual cycle.

The development of repetitive motor behaviors in deer mice: Effects of environmental enrichment, repeated testing, and differential mediation by indirect basal ganglia pathway activation.

Little is known about the mechanisms mediating the development of repetitive behaviors in human or animals. Deer mice reared with environmental enrichment (EE) exhibit fewer repetitive behaviors and greater indirect basal ganglia pathway activation as adults than those reared in standard cages. The developmental progression of these behavioral and neural circuitry changes has not been characterized. We assessed the development of repetitive behavior in deer mice using both a longitudinal and cohort design. Repeated testing negated the expected effect of EE, but cohort analyses showed that progression of repetitive behavior was arrested after 1 week of EE and differed significantly from controls after 3 weeks. Moreover, EE reductions in repetitive behavior were associated with increasing activation of indirect pathway nuclei in males across adolescence, but not females. These findings provide the first assessment of developmental trajectories within EE and support indirect pathway mediation of repetitive behavior in male deer mice.

Transgenerational effects of environmental enrichment on repetitive motor behavior development.

The favorable consequences of environmental enrichment (EE) on brain and behavior development are well documented. Much less is known, however, about transgenerational benefits of EE on non-enriched offspring. We explored whether transgenerational effects of EE might extend to the development of repetitive motor behaviors in deer mice. Repetitive motor behaviors are invariant patterns of movement that, across species, can be reduced by EE. We found that EE not only attenuated the development of repetitive behavior in dams, but also in their non-enriched offspring. Moreover, maternal behavior did not seem to mediate the transgenerational effect we found, although repetitive behavior was affected by reproductive experience. These data support a beneficial transgenerational effect of EE on repetitive behavior development and suggest a novel benefit of reproductive experience.

How does environmental enrichment reduce repetitive motor behaviors? Neuronal activation and dendritic morphology in the indirect basal ganglia pathway of a mouse model.

Repetitive motor behaviors are observed in many neurodevelopmental and neurological disorders (e.g., autism spectrum disorders, Tourette syndrome, fronto-temporal dementia). Despite their clinical importance, the neurobiology underlying these highly stereotyped, apparently functionless behaviors is poorly understood. Identification of mechanisms that mediate the development of repetitive behaviors will aid in the discovery of new therapeutic targets and treatment development. Using a deer mouse model, we have shown that decreased indirect basal ganglia pathway activity is associated with high levels of repetitive behavior. Environmental enrichment (EE) markedly attenuates the development of such aberrant behaviors in mice, although mechanisms driving this effect are unknown. We hypothesized that EE would reduce repetitive motor behaviors by increasing indirect basal ganglia pathway function. We assessed neuronal activation and dendritic spine density in basal ganglia of adult deer mice reared in EE and standard housing. Significant increases in neuronal activation and dendritic spine densities were observed only in the subthalamic nucleus (STN) and globus pallidus (GP), and only for those mice that exhibited an EE-induced decrease in repetitive motor behavior. As the STN and GP lie within the indirect pathway, these data suggest that EE-induced attenuation of repetitive motor behaviors is associated with increased functional activation of the indirect basal ganglia pathway. These results are consistent with our other findings highlighting the importance of the indirect pathway in mediating repetitive motor behaviors.

Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice.

As the genomic basis for Down syndrome (DS), human trisomy 21 is the most common genetic cause of intellectual disability in children and young people. The genomic regions on human chromosome 21 (Hsa21) are syntenic to three regions in the mouse genome, located on mouse chromosome 10 (Mmu10), Mmu16, and Mmu17. Recently, we have developed three new mouse models using chromosome engineering carrying the genotypes of Dp(10)1Yey/+, Dp(16)1Yey/+, or Dp(17)1Yey/+, which harbor a duplication spanning the entire Hsa21 syntenic region on Mmu10, Mmu16, or Mmu17, respectively. In this study, we analyzed the hippocampal long-term potentiation (LTP) and cognitive behaviors of these models. Our results show that, while the genotype of Dp(17)1Yey/+ results in abnormal hippocampal LTP, the genotype of Dp(16)1Yey/+ leads to both abnormal hippocampal LTP and impaired learning/memory. Therefore, these mutant mice can serve as powerful tools for further understanding the mechanism underlying cognitively relevant phenotypes associated with DS, particularly the impacts of different syntenic regions on these phenotypes.

Deficiencies in the region syntenic to human 21q22.3 cause cognitive deficits in mice.

Copy-number variation in the human genome can be disease-causing or phenotypically neutral. This type of genetic rearrangement associated with human chromosome 21 (Hsa21) underlies partial Monosomy 21 and Trisomy 21. Mental retardation is a major clinical manifestation of partial Monosomy 21. To model this human chromosomal deletion disorder, we have generated novel mouse mutants carrying heterozygous deletions of the 2.3- and 1.1-Mb segments on mouse chromosome 10 (Mmu10) and Mmu17, respectively, which are orthologous to the regions on human 21q22.3, using Cre/loxP-mediated chromosome engineering. Alterations of the transcriptional levels of genes within the deleted intervals reflect gene-dosage effects in the mutant mice. The analysis of cognitive behaviors shows that the mutant mice carrying the deletion on either Mmu10 or Mmu17 are impaired in learning and memory. Therefore, these mutants represent mouse models for Monosomy 21-associated mental retardation, which can serve as a powerful tool to study the molecular mechanism underlying the clinical phenotype and should facilitate efforts to identify the haploinsufficient causative genes.

A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions.

Down syndrome (DS) is caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is the most common genetic cause for developmental cognitive disability. The regions on Hsa21 are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this report, we describe a new mouse model for DS that carries duplications spanning the entire Hsa21 syntenic regions on all three mouse chromosomes. This mouse mutant exhibits DS-related neurological defects, including impaired cognitive behaviors, reduced hippocampal long-term potentiation and hydrocephalus. These results suggest that when all the mouse orthologs of the Hsa21 genes are triplicated, an abnormal cognitively relevant phenotype is the final outcome of the elevated expressions of these orthologs as well as all the possible functional interactions among themselves and/or with other mouse genes. Because of its desirable genotype and phenotype, this mutant may have the potential to serve as one of the reference models for further understanding the developmental cognitive disability associated with DS and may also be used for developing novel therapeutic interventions for this clinical manifestation of the disorder.

Mutation I810N in the alpha3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS.

In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/+ mice carry a mutation (I810N) which renders the normally expressed Na(+),K(+)-ATPase alpha3 isoform inactive. Total Na(+),K(+)-ATPase activity was reduced by 42% in Myk/+ brain. The epilepsy in Myk/+ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na(+),K(+)-ATPase alpha3 by transgenesis, which also rescued Na(+),K(+)-ATPase activity. Our findings reveal the functional significance of the Na(+),K(+)-ATPase alpha3 isoform in the control of epileptiform activity and seizure behavior.

Methods to rapidly and accurately screen a large number of ENU mutagenized mice for abnormal motor phenotypes.

In a dominant genetic screen for late-onset motor impairments in mice, 16-20-week-old N-nitroso-N-ethylurea (ENU)-mutagenized females were subjected to a behavioural test battery consisting of a visual assessment followed by the vertical pole, rotarod and grip strength tests. SOD1-G93A transgenic mice were tested in parallel as a positive control to provide information on the validity and sensitivity of the screen. From among the 1500 G1 ENU mice screened, four affected mice with impaired motor function were classified as outliers. Approximately 32% of the G2 and G3 progeny of one outlier were affected. Vertical pole, rotarod and grip strength test scores were significantly correlated with each other and with body weight in the G1 progeny, but the correlation with body weight was not maintained in the G2 and G3 progeny. We found that two tests, tail suspension and vertical pole, were sufficient to distinguish ENU outliers and SOD1-G93A hemizygotes from control mice, and could detect abnormalities earlier and more frequently than the other tests employed.

Effects of the rd1 mutation and host strain on hippocampal learning in mice.

Many of the inbred mouse strains commonly used in biomedical research are homozygous for the rd1 mutation of the Pde6b gene, which causes retinal degeneration. To dissociate the behavioural effects of rd1 homozygosity from those of the genetic background of the host strain in the most widely used paradigms for evaluating the cognitive abilities of mice, two rd1 homozygous strains (C3H/HeJ and CBA/J) were compared with two Pde6b wild-type strains, each possessing a genetic background identical (C3A.BLiA-Pde6b+/J) or very similar (CBA/CaJ) to that of its rd1 homozygous relative. In the fear conditioning procedure, the presence of the rd1 mutation had no effect on performance at any stage, as the superior contextual learning of the CBA/J and CBA/CaJ strains could be explained by genetic background effects alone. In the Morris water maze, only the Pde6b wild-type C3A.BLiA-Pde6b+/J and CBA/CaJ strains were able to demonstrate spatial learning. The study thus demonstrates how retinal degeneration and genetic background have different effects in these two tests of hippocampus-dependent learning and memory.

NIH Swiss and Black Swiss mice have retinal degeneration and performance deficits in cognitive tests.

Swiss mice are among the most commonly used outbred strains in biomedical research. Because prior knowledge of the baseline phenotypes of mouse strains will allow informed selection of strains for particular experiments, we sought to characterize the behavior of two previously untested outbred Swiss strains--NIH Swiss and Black Swiss--in the two most widely used paradigms for evaluating the cognitive abilities of mice. Unlike the C57BL/6J and C57BL/6J-Tyr(c-2J) controls, animals of both outbred Swiss strains were unable to demonstrate learning in the Morris water maze and contextual fear conditioning paradigms. A polymerase chain reaction assay revealed that all of the NIH Swiss and Black Swiss mice tested were homozygous for the recessive retinal degeneration 1 mutation of the Pde6b gene. Histological examination of NIH Swiss and Black Swiss mouse eyes confirmed the presence of retinal degeneration, which causes visual image blindness. These findings indicate that NIH Swiss and Black Swiss mice are visually im paired and thus may be unsuitable for use in some experiments.