The striatal dopamine signal has multiple facets; tonic level, phasic rise and fall, and variation of the phasic rise/fall depending on the expectation of reward/punishment. We have developed a network model of the striatal direct pathway using an ionic current level model of the medium spiny neuron that incorporates currents sensitive to changes in the tonic level of dopamine. The model neurons in the network learn action selection based on a novel set of mathematical rules that incorporate the phasic change in the dopamine signal. This network model is capable of learning to perform a sequence learning task that in humans is thought to be dependent on the basal ganglia. When both tonic and phasic levels of dopamine are decreased, as would be expected in unmedicated Parkinson’s disease (PD), the model reproduces the deficits seen in a human PD group off medication. When the tonic level is increased to normal, but with reduced phasic increases and decreases in response to reward and punishment respectively, as would be expected in PD medicated with L-Dopa, the model again reproduces the human data. These findings support the view that the cognitive dysfunctions seen in Parkinson’s disease are not solely due to either the decreased tonic level of dopamine or to the decreased responsiveness of the phasic dopamine signal to reward and punishment, but to a combination of the two factors that varies dependent on disease stage and medication status.
Striatum; Dopamine; Computational model; Learning; Parkinson’s disease
•Fornix damage mildly impair spatial biconditional and passive place learning tasks.•Fornix lesions impair spatial go/no-go and alternation problems.•Fornix lesions impair tests making flexible demands on spatial memory.•Fornix connections are not always required for learning fixed spatial responses.
The present study sought to understand how the hippocampus and anterior thalamic nuclei are conjointly required for spatial learning by examining the impact of cutting a major tract (the fornix) that interconnects these two sites. The initial experiments examined the consequences of fornix lesions in rats on spatial biconditional discrimination learning. The rationale arose from previous findings showing that fornix lesions spare the learning of spatial biconditional tasks, despite the same task being highly sensitive to both hippocampal and anterior thalamic nuclei lesions. In the present study, fornix lesions only delayed acquisition of the spatial biconditional task, pointing to additional contributions from non-fornical routes linking the hippocampus with the anterior thalamic nuclei. The same fornix lesions spared the learning of an analogous nonspatial biconditional task that used local contextual cues. Subsequent tests, including T-maze place alternation, place learning in a cross-maze, and a go/no-go place discrimination, highlighted the impact of fornix lesions when distal spatial information is used flexibly to guide behaviour. The final experiment examined the ability to learn incidentally the spatial features of a square water-maze that had differently patterned walls. Fornix lesions disrupted performance but did not stop the rats from distinguishing the various corners of the maze. Overall, the results indicate that interconnections between the hippocampus and anterior thalamus, via the fornix, help to resolve problems with flexible spatial and temporal cues, but the results also signal the importance of additional, non-fornical contributions to hippocampal-anterior thalamic spatial processing, particularly for problems with more stable spatial solutions.
Biconditional learning; Cognitive map; Configural learning; Hippocampus; Incidental learning; Thalamus
Genetically-modified animal models are a powerful tool for investigating the link between neurological and behavioral changes and for the development of therapeutic interventions. Executive function deficits are symptomatic of many human clinical disorders but few tasks exist for studying executive functions in mice. To address this need, we describe procedures for establishing Pavlovian contextual and instrumental biconditional discriminations (BCDs) in C57BL/6J mice. In the first experiment, contextual cues disambiguated when two short duration stimulus targets would be followed by food pellets. In the second experiment, discrete visual cues signaled when lever press or nose poke responses would be continuously reinforced with food pellets. Mice learned both BCDs as evidenced by differential responding in each cue during training and, more critically, during extinction testing. The implications of these findings for using BCD tasks to analyze the neural substrates of executive processing in animal models are discussed.
biconditional; context; executive; extinction; hierarchical; instrumental
We present a 2-day water maze protocol that addresses some of potential confounds present in the water maze when using the aged subjects typical of studies of neurodegenerative disorders, such as Alzheimer’s disease. This protocol is based on an initial series of training trials with a visible platform, followed by a memory test with a hidden platform 24 h later. We validated this procedure using aged (15–18 m) mice expressing three Alzheimer’s disease-related transgenes, PS1(M146 V), APP(Swe), and tau(P301L). We also tested these triple transgenic mice (3xTG) and age and sex-matched wild-type (WT) in a behavioral battery consisting of tests of motor coordination (balance beam), spatial memory (object displacement task) visual acuity (novel object recognition task) and locomotor activity (open field). 3xTG mice had significantly longer escape latencies in the memory trial of the 2-day water maze test than WT and than their own baseline performance in the last visible platform trial. In addition, this protocol had improved sensitivity compared to a typical probe trial, since no significant differences between genotypes were evident in a probe trial conducted 24 h after the final training trial. The 2-day procedure also resulted in good reliability between cohorts, and controlled for non-cognitive factors that can confound water maze assessments of memory, such as the significantly lower locomotor activity evident in the 3xTG mice. A further benefit of this method is that large numbers of animals can be tested in a short time.
Aging; Novel object placement task; Novel object recognition task; Spatial memory; Alzheimer’s disease; Sex differences; Water maze
Prostacyclin is an endogenous lipid metabolite with properties of vasodilation and anti-platelet aggregation. While the effects of prostacyclin on the vascular protection have been well-documented, the role of this eicosanoid in the central nervous system has not been extensively studied. Recently, a transgenic mouse containing a hybrid enzyme, of cyclooxygenase-1 linked to prostacyclin synthase, was developed that produces elevated levels of prostacyclin in vivo. The goal of this study was to investigate whether increased prostacyclin biosynthesis could affect behavioral phenotypes in mice. Our results uncovered that elevated levels of prostacyclin broadly affect both cognitive and non-cognitive behaviors, including decreased anxiety-like behavior and improved learning in the fear-conditioning memory test. This study demonstrates that prostacyclin plays an important, but previously unrecognized, role in central nervous system function and behavior.
Prostacyclin; eicosanoid; behavior; memory; anxiety
The hippocampus is known to be especially sensitive to the deleterious effects of glucocorticoids. Previously, we administered exogenous corticosterone, the major stress-related glucocorticoid in rats, to young developing rats using subcutaneous pellets which produced high pharmacological levels of circulating corticosterone as well as a sex-specific learning deficit for males on a hippocampus-mediated associative learning task, trace eyeblink conditioning . The present study evaluated the effects of corticosterone administered at a physiologically-relevant level by a more consistent release method, osmotic mini-pumps. Pumps were implanted subcutaneously in 15-day-old rats to deliver either corticosterone or the vehicle control (PEG) at a rate of 1μL/hour over 3 days. On Day 28, learning was assessed using trace eyeblink conditioning. The results of the present experiment revealed that a small elevation in corticosterone (11.77 μg/dl vs 6.02 μg/dl for controls) within the normal physiological range impaired learning as determined by a significantly lower percentage and amplitude of total conditioned responses (CRs) and lower amplitude of adaptive responses relative to the control group. There were no significant differences in response timing, although the corticosterone group tended to produce CRs which began and peaked a little later than controls. These findings indicate that even modest elevations of corticosterone for several days can produce later impairments on this hippocampally mediated learning task.
trace conditioning; eyeblink; corticosterone; hippocampus; development; learning
Previous studies in both humans and animals have documented improved performance following discrimination training. This enhanced performance is often associated with cortical response changes. In this study, we tested the hypothesis that long-term speech training on multiple tasks can improve primary auditory cortex (A1) responses compared to rats trained on a single speech discrimination task or experimentally naïve rats. Specifically, we compared the percent of A1 responding to trained sounds, the responses to both trained and untrained sounds, receptive field properties of A1 neurons, and the neural discrimination of pairs of speech sounds in speech trained and naïve rats. Speech training led to accurate discrimination of consonant and vowel sounds, but did not enhance A1 response strength or the neural discrimination of these sounds. Speech training altered tone responses in rats trained on six speech discrimination tasks but not in rats trained on a single speech discrimination task. Extensive speech training resulted in broader frequency tuning, shorter onset latencies, a decreased driven response to tones, and caused a shift in the frequency map to favor tones in the range where speech sounds are the loudest. Both the number of trained tasks and the number of days of training strongly predict the percent of A1 responding to a low frequency tone. Rats trained on a single speech discrimination task performed less accurately than rats trained on multiple tasks and did not exhibit A1 response changes. Our results indicate that extensive speech training can reorganize the A1 frequency map, which may have downstream consequences on speech sound processing.
Speech; Primary auditory cortex; Plasticity; Training
A single central injection of angiotensin II (AngII) potently increases water intake; however, a growing body of research suggests that repeated, acute intracerebroventricular injections of AngII cause a reduction in the dipsogenic response to subsequent AngII. This AngII-induced behavioral desensitization is specific to the effects of angiotensin and mediated by the angiotensin type-1 (AT1) receptor. The neuroanatomical substrate for this phenomenon, however, remains unknown. The anteroventral third ventricle region (AV3V) is an important site for the behavioral and physiological actions of AngII. Therefore, we hypothesized that this region also mediates the effects of repeated central AngII administration. In support of this hypothesis, we found that repeated injections of AngII into the AV3V reduced water intake stimulated by a test injection of AngII given into this region. Moreover, repeated AngII injections in the AV3V reduced water intake after AngII was injected into the lateral ventricle. These studies also demonstrate that activation of the AT1 receptor within the AV3V is required for AngII-induced behavioral desensitization because direct injection of the AT1 receptor antagonist, losartan, into the AV3V blocked the desensitizing effect of repeated AngII injections into the lateral ventricle. These findings provide additional support for a role of the AV3V in the dipsogenic actions of AngII, and suggest that this region is critical for the desensitization that occurs after acute repeated central injections of AngII.
AV3V; angiotensin; desensitization; thirst
Using an event-triggered recording system, the quantity of daily song bout production was measured weekly in male zebra finches (Taeniopygia guttata) during sensory-motor learning and at one year of age. Our aim was to ask whether the development of a stereotyped vocal pattern involves a practice-driven component. If so, we hypothesized that juvenile males learning song should sing more often than adults reciting a vocal pattern they had already learned, and that greater levels of juvenile singing should be associated with improvement in the quality of the adult song. Across the period measured (36–365 days of age), subjects showed an inverted U-shaped pattern of daily song bout production. Song bout production was lowest during subsong, with increased production associated with plastic song and song crystallization, although individual differences were large. Daily song bout production decreased in adulthood. Higher levels of song bout production during plastic song correlated with fewer sequencing errors in adult song patterns (r2=0.77). In contrast, quantity of singing during song crystallization showed no relationship to vocal stereotypy (r2=0.002). Our data suggest a sensitive period for vocal practice during zebra finch sensory-motor learning with consequences for the note-sequence fidelity of the adult vocal pattern.
Songbird; Learning; Juvenile; Sensitive period; Vocal production; Circadian
Environmental enrichment attenuates the response to psychostimulants and has been shown to reduce both anxiety and stress-related behaviors. Since stress is a major vulnerability factor for addiction, we investigated whether enrichment could reverse stress profiles in high anxious rats as well as reduce their amphetamine sensitivity. Using selectively-bred high and low anxiety males (filial 3) from enriched, social or isolated environments, we tested elevated plus maze exploration, novelty place preference and amphetamine (AMPH; 0.5 mg/kg, IP)-induced hyperactivity. We measured plasma corticosterone (CORT) response after forced novel object exposure, phosphorylation of the tropomyosin-related kinase B receptor (pTrkB) in the hippocampus and striatum, and dopamine (D2) receptor mRNA levels in the striatum and nucleus accumbens. Results indicate that high anxiety animals reared in social or enriched environments spent more time on open arms of the EPM while low anxiety animals raised in enriched environments spent more time on open arms when compared to either isolated or social groups. There were no group differences or interactions found for novelty place preference. Enriched environments decreased the response to AMPH and stress-induced CORT regardless of trait but selectively decreased pTrkB and increased D2 mRNA levels in high anxiety animals. The results suggest that selectively-bred trait anxiety rats show state anxiety that is influenced by rearing environments, and D2 protein levels and BDNF/TrkB signaling may differentially contribute to integrating these effects.
ANXIETY; BDNF; ELEVATED PLUS MAZE; ADDICTION; DOPAMINE RECEPTOR
Narp knockout (KO) mice demonstrate cognitive inflexibility and addictive behavior, which are associated with abnormal reactivity to a novel stimulus. To assess reactivity to novelty, we tested Narp KO and wild-type (WT) mice on a neophobia procedure. Both Narp KO and WT mice showed a similar decrease in consumption upon initial exposure to a novel flavor, but Narp KO mice did not increase consumption with subsequent exposures to the novel flavor like the WT mice. Therefore, Narp KO mice do not have abnormal reactivity to novelty but show deficits in adapting behavior to reflect the updated value of a stimulus.
Narp; neophobia; extinction; novelty; addiction; recovery from neophobia
The basal ganglia are thought to play a critical role in duration perception and production. However, experimental evidence for impaired temporal processing in Parkinson’s disease (PD) patients is mixed. This study examined the association between striatal dopaminergic denervation in PD patients and sensorimotor synchronization. Twenty-eight mild-to-moderate stage PD patients synchronized finger taps to tone sequences of either 500 ms, 1000 ms or 1500 ms time intervals while ON levodopa (L-DOPA) or placebo pill (on separate test days) with the index finger of their more and less affected hands. We measured the accuracy and variability of synchronization. In a separate session, patients underwent 11C-dihydrotetrabenazine (11C-DTBZ) PET scanning to measure in vivo striatal dopaminergic denervation. Patients were less accurate synchronizing to the 500 ms target time interval, compared to the 1000 and 1500 ms time intervals, but neither medication state nor hand affected accuracy; medication state, hand nor the target time interval affected synchronization variability. Regression analyses revealed no strong relationships between synchronization accuracy or variability and striatal dopaminergic denervation. We performed a cluster analysis on the degree of dopaminergic denervation to determine whether patient subgroup differences underlie our results. Three patient subgroups showed behavioral differences in synchronization accuracy, but not variability, paralleling their pattern of denervation. These findings provide further evidence for the role of the basal ganglia and dopamine in duration production and suggest that the degree of striatal dopaminergic denervation may explain the heterogeneity of performance between PD patients on the sensorimotor synchronization task.
Positron emission tomography; Dopaminergic denervation; Parkinson’s disease; Basal ganglia; Paced finger tapping; Duration production
This study compared nicotine intake and changes in food intake and weight gain in naïve adolescent, naïve adult, and adult rats that were exposed to nicotine during adolescence. An extended intravenous self-administration (IVSA) model was used whereby rats had 23-hour access to saline or increasing doses of nicotine (0.03, 0.06, and 0.09 mg/kg/0.1 mL infusion) for 4-day intervals separated by 3-day periods of abstinence. Rats began IVSA as adolescents (PND 32–34) or adults (PND 75). A separate group of rats was exposed to nicotine via osmotic pumps (4.7 mg/kg) for 14 days during adolescence and then began nicotine IVSA as adults (PND 75). The rats that completed the nicotine IVSA regimen were also tested for nicotine-seeking behavior during extinction. The results revealed that nicotine intake was highest in adolescents followed by adults that were pre-exposed to nicotine during adolescence as compared to naïve adults. A similar pattern of nicotine-seeking behavior was observed during extinction. In contrast to nicotine intake, naïve adults displayed robust appetite and weight suppressant effects of nicotine, an effect that was absent in adolescents and adults that were pre-exposed to nicotine during adolescence. Our findings suggest that adolescence is a unique period of enhanced vulnerability to the reinforcing effects of nicotine. Although adolescents gain weight faster than adults, the food intake and weight suppressant effects of nicotine are reduced during adolescence. Importantly, our findings suggest that adolescent nicotine exposure produces long-lasting consequences that enhance nicotine reward and promote tolerance to the anorectic effects of this drug.
Age; Adolescent; Pre-exposure; Intravenous; Weight; Food intake
Compared to socially housed (SH) rats, adult isolation-reared (IR) rats exhibit phenotypes relevant to schizophrenia (SZ), including reduced prepulse inhibition (PPI) of startle. PPI is normally regulated by the medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). We assessed PPI, auditory-evoked local field potentials (LFPs) and expression of 7 PPI- and SZ-related genes in the mPFC and NAC, in IR and SH rats. Buffalo (BUF) rats were raised in same-sex groups of 2–3 (SH) or in isolation (IR). PPI was measured early (d53) and later in adulthood (d74); LFPs were measured approximately on d66. Brains were processed for RT-PCR measures of mPFC and NAC expression of Comt, Erbb4, Grid2, Ncam1, Slc1a2, Nrg1 and Reln. Male IR rats exhibited PPI deficits, most pronounced at d53; male and female IR rats had significantly elevated startle magnitude on both test days. Gene expression levels were not significantly altered by IR. PPI levels (d53) were positively correlated with mPFC expression of several genes, and negatively correlated with NAC expression of several genes, in male IR but not SH rats. Late (P90) LFP amplitudes correlated significantly with expression levels of 6/7 mPFC genes in male rats, independent of rearing. After IR that disrupts early adult PPI in male BUF rats, expression levels of PPI- and SZ-associated genes in the mPFC correlate positively with PPI, and levels in the NAC correlate negatively with PPI. These results support the model that specific gene-behavior relationships moderate the impact of early-life experience on SZ-linked behavioral and neurophysiological markers.
catechol-O-methyltransferase; isolation rearing; medial prefrontal cortex; nucleus accumbens; prepulse inhibition; schizophrenia
When an antipsychotic drug is given repeatedly and intermittently, there is often a long-term increase in its behavioral efficacy, termed antipsychotic sensitization. With the passage of time, the magnitude of antipsychotic sensitization may increase or decrease depending on the principle of Time-Dependent Sensitization (TDS) or memory decay, respectively. In the present study, we examined the time-dependent feature and possible dopamine D2 receptor mechanism of sensitization induced by the antipsychotics risperidone and asenapine in the conditioned avoidance response test. Well-trained male adult Sprague-Dawley rats were first repeatedly treated with risperidone (1.0 mg/kg) or asenapine (0.2 mg/kg) and tested for avoidance response daily for 5 consecutive days. Eight, 18 or 38 days after the 5th drug treatment, all rats were retested drug-free to assess the residual impact of prior risperidone or asenapine treatment. Drug-pretreated rats had significantly lower avoidance than vehicle-pretreated ones on this test, and the group differences increased with the passage of time. In the subsequent drug challenge test at 10, 20 or 40 days after the 5th drug treatment, all rats were injected with a low dose of risperidone (0.3 mg/kg) or asenapine (0.1 mg/kg). Drug-pretreated rats again made significantly less avoidances than controls, confirming the drug-induced sensitization effect. Finally, in the quinpirole (a D2/3 receptor agonist, 1.0 mg/kg, sc)-induced hyperlocomotion test, risperidone-pretreated rats exhibited a significantly higher level of motor activity than the vehicle-pretreated ones. These findings suggest that risperidone and asenapine sensitization is long-lasting, follows the TDS principle, and is likely mediated by D2 receptor supersensitivity.
Time-Dependent Sensitization (TDS); Asenapine; Risperidone; Conditioned avoidance response; Quinpirole; Locomotor activity