Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice.

Serotonin systems have been implicated in the regulation of hippocampal function. Serotonin 5-HT2C receptors are widely expressed throughout the hippocampal formation, and these receptors have been proposed to modulate synaptic plasticity in the visual cortex. To assess the contribution of 5-HT2C receptors to the serotonergic regulation of hippocampal function, mice with a targeted 5-HT2C-receptor gene mutation were examined. An examination of long-term potentiation at each of four principal regions of the hippocampal formation revealed a selective impairment restricted to medial perforant path-dentate gyrus synapses of mutant mice. This deficit was accompanied by abnormal performance in behavioral assays associated with dentate gyrus function. 5-HT2C receptor mutants exhibited abnormal performance in the Morris water maze assay of spatial learning and reduced aversion to a novel environment. These deficits were selective and were not associated with a generalized learning deficit or with an impairment in the discrimination of spatial context. These results indicate that a genetic perturbation of serotonin receptor function can modulate dentate gyrus plasticity and that plasticity in this structure may contribute to neural mechanisms underlying hippocampus-dependent behaviors.

Defective motor behavior and neural gene expression in RIIbeta-protein kinase A mutant mice.

Motor behavior is modulated by dopamine-responsive neurons in the striatum, where dopaminergic signaling uses G-protein-coupled pathways, including those that result in the activation of cAMP-dependent protein kinase (PKA). The RIIbeta isoform of PKA is highly enriched in the striatum, and targeted disruption of the RIIbeta gene in mice leads to a dramatic reduction in total PKA activity in this region. Although the mutant mice show typical locomotor responses after acute administration of dopaminergic drugs, they display abnormalities in two experience-dependent locomotor behaviors: training on the rotarod task and locomotor sensitization to amphetamine. In addition, amphetamine induction of fos is absent, and the basal expression of dynorphin mRNA is reduced in the striatum. These results demonstrate that motor learning and the regulation of neuronal gene expression require RIIbeta PKA, whereas the acute locomotor effects of dopaminergic drugs are relatively unaffected by this PKA deficiency.

Genetic correlation between performance on an appetitive-signaled nosepoke task and voluntary ethanol consumption.

The present study used a signaled appetitive nosepoke task as a measure of behavioral control or impulsivity related to reward system function in mice and determined how impulsivity correlated with voluntary ethanol consumption. Thirteen inbred strains were trained to nosepoke for food rewards and eventually trained to nosepoke for reward when an auditory signal was presented. Efficiency in the signaled nosepoke task indicated the ability of the mice to withhold the nosepoke response until the signal to respond for a reward was given and was considered indicative of behavioral control or impulsivity. After completion of the nosepoke task, the mice were tested for ethanol consumption in a three-bottle choice test at 3 and 10% (v/v) ethanol concentrations. Behavioral measures from the nosepoke task and ethanol consumption measures were correlated to determine a genetic relationship. High efficiency, the ability to withhold nosepoking until signaled, was negatively correlated with ethanol consumption. Thus, the strains who were better able to control their behavioral responding (i.e., less impulsive) consumed less ethanol, and strains who were more impulsive consumed more ethanol. This genetic relationship may be a mouse behavioral model for some of the neuropsychological traits demonstrated in human subjects who are family history-positive for alcoholism.

Assessment of locomotor activity, acoustic and tactile startle, and prepulse inhibition of startle in inbred mouse strains and F1 hybrids: implications of genetic background for single gene and quantitative trait loci analyses.

As the use of transgenic and null mutation techniques in the development of animal models of disorders increases, the importance of selecting the appropriate genetic background also increases. The genetic background of the mouse strains used as models for various disorders is critical because of the potential for epistatic effects on the expression of transgenes and null mutations. Twelve strains of inbred mice and seven F1 hybrids were tested in multiple behavioural tasks including open-field locomotor activity, Y-maze activity, auditory and tactile startle and prepulse inhibition of startle response. Differences across genotypes were found for all variables measured. The range of variability among genotypes was dependent on the specific measure so careful consideration must be made in selecting a strain for testing a particular behaviour. Because of the polygenic nature of each of the behavioural phenotypes, the impact of a single gene manipulation may vary depending on the genetic background on which it is expressed. Moreover, quantitative trait loci methods could be applied to these behaviours.

Assessment of learning by the Morris water task and fear conditioning in inbred mouse strains and F1 hybrids: implications of genetic background for single gene mutations and quantitative trait loci analyses.

Genetic methods including the creation of transgenic or null mutant models and mapping studies using quantitative trait loci strategies can be used to identify candidate genes in mice that regulate learning processes. Interpretations as to the impact of single gene mutations for polygenic behaviours like learning will depend in part on the genetic background of the animals used for these manipulations. To address the issue of genetic variability, 12 inbred strains and seven different F1 hybrids were tested on multiple behavioural tasks, including two complex learning paradigms: the Morris water task and fear conditioning. Strain differences were found for all variables measured. In the hidden platform version of the Morris task, the albino animals performed poorly while overall the F1 hybrids showed the best selectivity for the trained quadrant as measured in a probe trial. In contrast, almost all genotypes performed well on the contextual fear conditioning task and learned to associate the test context with the pairing of a foot shock and auditory stimulus as demonstrated 24 h after training by increased freezing in the test environment compared to an altered context. Significant genetic correlations were obtained for behavioural measures suggesting that the same genes regulate various aspects of performance on behavioural tasks. Scores from these multiple inbred strains and F1 hybrids provide a baseline level of learning ability for fear conditioning and the Morris water task. The results of the present study confirm the importance of genetic background in the performance of various learning tasks. This variability should be considered when developing new transgenic or null mutant animal models.

Hippocampal lesions cause learning deficits in inbred mice in the Morris water maze and conditioned-fear task.

This study examined the effect of hippocampal lesions on acquisition of the Morris water maze and conditioned-fear task in inbred mice. C57BL/6J, DBA/2J, and B6D2F1 hybrid mice were given hippocampal lesions or sham surgery and then tested. The lesioned C57BL/6J and B6D2F1 mice failed to learn the Morris task relative to sham-operated controls, and no DBA group learned the task. In the contextual component of conditioned fear, lesions decreased freezing in all strains. But the lesions only affected freezing to the conditioned stimulus in the DBA/2J and B6D2F1 strains. These data demonstrate that C57BL/6J and B6D2F1 mice use the hippocampus to solve the Morris water maze and conditioned-fear task, and the DBA mice use the hippocampus, to some degree, in the conditioned-fear task.

Involvement of the ventrolateral thalamic nucleus in rabbit classical eyeblink conditioning.

The involvement of the ventrolateral nucleus of the thalamus in relaying learning-related activity to higher brain structures during classical conditioning of the rabbit eyelid response was examined in two experiments. In the first study, multiple-unit ventrolateral thalamic nucleus activity was monitored before and after lesions of either the cerebellar interpositus nucleus or red nucleus were given. Before the lesions were given, conditioned response-related activity was observed in the ventrolateral thalamic nucleus. Lesions of the interpositus nucleus, but not the red nucleus, disrupted the conditioning-related activity in the ventrolateral thalamic nucleus, thus suggesting that an efferent copy of conditioned response-related activity is projected directly from the interpositus nucleus to higher brain areas by way of the ventrolateral thalamic nucleus. In the second study, multiple unit activity in the hippocampus was monitored before and after lesions were placed in the ventrolateral thalamic nucleus or red nucleus. Conditioning-related activity in the hippocampus was not affected by either lesion, thus suggesting that maintenance of training-related activity in the hippocampus is not critically dependent on cerebellar information relayed through the ventrolateral thalamic nucleus or red nucleus.

Maze learning and morphology of frontal cortex in adult and aged basal forebrain-lesioned rats.

Maze performance and morphology of frontal cortex were assessed in young adult, middle-aged, and aged rats with and without lesions of the nucleus basalis magnocellularis. Although maze performance did not vary with age, neuron number and the thickness of superficial laminae were reduced in aged rats. Lamina II-III neurons were hypertrophied in middle-aged rats relative to both younger and older groups. At all ages, lesions significantly impaired maze performance. In young adult rats, lesions moderately reduced the size of lamina II-III neurons. This effect was more pronounced in middle-aged rats. Lesions in aged rats did not affect neuron size. The neuronal changes seen in middle-aged rats may reflect a compensatory response to the expression of other age-related neuronal changes, which may affect the ability of cortical neurons to respond to lesion-induced loss of cholinergic input.

Using signaled barpressing tasks to study the neural substrates of appetitive and aversive learning in rats: behavioral manipulations and cerebellar lesions.

The development of standard within-subject conditioning tasks for studying similarities and differences in the neural substrates of appetitive and aversive learning is described. Rats learned to press a bar during a brief tone presentation to receive a food pellet reward (the appetitive task). Using the same tone signal, conditioning chamber, and trial timing parameters, the same rats were then trained to press the bar during the tone presentation to avoid a mild footshock (the aversive task). As an initial study of the neural substrates of these forms of learning, the involvement of the cerebellum was assessed. Bilateral lesions of the deep cerebellar nuclei prevented the learning of the aversive task but had no effect on the learning of the appetitive task.

Rabbit classically conditioned eyelid responses do not reappear after interpositus nucleus lesion and extensive post-lesion training.

The left eyelid responses of four rabbits were classical conditioned by pairing a tone conditioned stimulus and air puff unconditioned stimulus. After conditioned responses were well-established, the left interpositus nucleus was lesioned and 150-200 post-lesion training sessions, distributed over 10 months, were given. In three of the rabbits, no anticipatory conditioned responses were observed on paired trials and responses were at or below spontaneous blinking rates on 2,500 ms CS-alone trials that were also presented. Post-lesion conditioned responses were present when the right side was trained. The fourth rabbit showed few post-lesion conditioned responses on paired trials but eventually showed 80% conditioned responses on tone-alone trials. Histological analysis of the lesion extents indicate that a portion of the anterior interpositus nucleus was spared in this rabbit. These results argue that unlike other cerebellar lesion effects reported in the literature, where some recovery of function is normally noted, the effects of interpositus nucleus lesions are somewhat unique in that conditioned response abolition is seen as long as 10 months after the lesion.