Light onset can be both a sensory reinforcer (SR) with intrinsic reinforcing properties, and a conditioned reinforcer (CR) which predicts a biologically important reinforcer. Stimulant drugs, such as methamphetamine (METH), may increase the reinforcing effectiveness of CRs by enhancing the predictive properties of the CR. In contrast, METH-induced increases in the reinforcing effectiveness of SRs, are mediated by the immediate sensory consequences of the light.
The effects of novelty (on SRs) and METH (on both CRs and SRs) were tested. Experiment 1: Rats were pre-exposed to 5 s light and water pairings presented according to a variable-time (VT) 2 min schedule or unpaired water and light presented according to independent, concurrent VT 2 min schedules. Experiment 2: Rats were pre-exposed to 5 s light presented according to a VT 2 min schedule, or no stimuli. In both experiments, the pre-exposure phase was followed by a test phase in which 5 s light onset was made response-contingent on a variable-interval (VI) 2 min schedule and the effects of METH (0.5 mg/kg) were determined.
Novel light onset was a more effective reinforcer than familiar light onset. METH increased the absolute rate of responding without increasing the relative frequency of responding for both CRs and SRs.
Novelty plays a role in determining the reinforcing effectiveness of SRs. The results are consistent with the interpretation that METH-induced increases in reinforcer effectiveness of CRs and SRs may be mediated by immediate sensory consequences, rather than prediction.
Rats; Drug Abuse; Psychomotor Stimulant; Operant Conditioning; Pavlovian Conditioning; Dopamine
In addition to its cardinal symptoms of bradykinesia, muscle rigidity, resting tremor and postural disturbances, Parkinson’s disease (PD) also affects orolingual motor function. Orolingual motor deficits can contribute to dysphagia, which increases morbidity and mortality in this population. Previous preclinical studies describing orolingual motor deficits in animal models of PD have focused on unilateral nigrostriatal dopamine (DA) depletion. In this study we compared the effects of unilateral vs bilateral 6-hydroxydopamine (6-OHDA)-induced DA depletion in rats trained to lick water from an isometric force-sensing disc. Rats received either unilateral or bilateral 6-OHDA into the medial forebrain bundle and were tested for four weeks post-lesion. Dependent variables included task engagement (the number of licks per session), tongue force (mean and maximum), and tongue motility (the number of licks per second). While both lesion groups exhibited decreased tongue force output, tongue motility deficits were present in only the group that received unilateral nigrostriatal DA depletion. Task engagement was not significantly diminished by 6-OHDA. Analysis of striatal DA tissue content revealed that DA depletion was ~97% in the unilateral group and ~90% in the bilateral group. These results suggest that while nigrostriatal DA depletion affects tongue force output, deficits in tongue motility may instead result from a functional imbalance in neural pathways affecting this midline structure.
Parkinson’s disease; orolingual; oromotor; isometric; operant; behavioral; nigrostriatal; dysarthria; dysphagia; force
The corpus callosum (CC) is the major white matter tract that connects the two cerebral hemispheres. Some have theorized that individual differences in behavioral and brain asymmetries are linked to variation in the density of axon fibers that traverse different sections of the CC. In this study, we examined whether variation in axon fiber density in the CC was associated with variation in asymmetries in the planum temporale (PT) in a sample of 20 post-mortem chimpanzee brains. We further tested for sex differences in small and large CC fiber proportions and density in the chimpanzees. We found that the distribution of small and large fibers within the CC of chimpanzees follows a similar pattern to those reported in humans. We also found that chimpanzees with larger asymmetries in the PT had fewer large fibers in the posterior portion of the CC, particularly among females. As has been reported in human brains, the findings reported here indicate that individual differences in brain asymmetries are associated with variation in interhemispheric connectivity as manifest in axon fiber density and size.
Chimpanzees; brain asymmetry; corpus callosum; axon fiber density; planum temporale
We recently observed that naloxone, a non-specific opioid antagonist, attenuated operant responding to ethanol in infant rats. Through the use of an operant conditioning technique, we aimed to analyze the specific participation of mu, delta, and kappa opioid receptors on ethanol reinforcement during the second postnatal week. In Experiment 1, infant rats (PDs 14–17) were trained to obtain 5, 7.5, 10, or 15% ethanol, by operant nose-poking. Experiment 2 tested blood ethanol levels (BELs) attained by operant behavior. In Experiment 3, at PDs16–18, rats received CTOP (mu antagonist: 0.1 or 1.0 mg/kg), naltrindole (delta antagonist: 1.0 or 5.0 mg/kg) or saline before training. In Experiment 4, rats received nor-binaltorphimine (kappa antagonist: 10.0 or 30.0 mg/kg, a single injection after completion of PD15 operant training), spiradoline mesylate (kappa agonist: 1.0 or 5.0 mg/kg; at PDs16–18) or saline (PDs16–18), before the conditioning. Experiment 5 and 6 assessed possible side effects of opioid drugs in locomotor activity (LA) and conditioned taste aversion (CTA). Ethanol at 7.5 and 10% promoted the highest levels of operant responding. BELs were 12–15 mg/dl. In Experiment 3 naltrindole (dose response effect) and CTOP (the lowest dose) were effective in decreasing operant responding. Nor-binaltorphimine at 10.0 mg/kg and spiradoline at 5.0 mg/kg also blocked ethanol responding. The effects of opioid drugs on ethanol reinforcement cannot be explained by effects on LA or CTA. Even though particular aspects of each opioid receptor require further testing, a fully functional opioid system seems to be necessary for ethanol reinforcement, during early ontogeny.
Ethanol reinforcement; infant rat; mu; delta and kappa opioid receptors; operant conditioning
Adolescence is a developmental period in which brain structures involved with stress responses, such as the medial pre-frontal cortex (mPFC), mature. Therefore, exposure to a stressor at this time may have effects that endure the lifespan. The goal of the present study was to determine whether behavioral control over an adolescent stressor mitigates the behavioral and neurochemical consequences of the stressor as occurs in adult rats. Adolescent rats (post natal day 35) were exposed to either inescapable (IS) or escapable tailshocks (ES). As in adults we observed a “stressor controllability effect”; IS reduced social exploration and activated the serotonergic dorsal raphé nucleus while ES did not. Excitotoxic lesions of the medial prefrontal cortex prevented the stressor controllability effect. We also demonstrate that a controllable adolescent stress prevents the behavioral and neurochemical consequences of IS in adulthood. Thus, the controllability of a stressor during adolescence is an important psychological factor.
Learned Helplessness; Stress; Adolescence; Serotonin; Social Interaction; Stressor Controllability
Although D1 receptor knockout mice demonstrate normal morphine place preferences, antagonism of basolateral amygdala (BLA) D1 receptors only during drug-naive rat conditioning has been reported to inhibit the expression of a morphine place preference. One possible explanation for this result is state-dependent learning. That is, the omission of the intra-BLA infusion cue during testing — which acts as a potent discriminative stimulus — may have prevented the recall of a morphine-environment association and therefore, the consequent expression of a morphine place preference. To examine this possibility, we tested whether intra-BLA infusion of the D1-receptor antagonist SCH23390 during both training and testing might reveal a morphine place preference. Our results suggest that in previously drug-naive animals, D1 receptor antagonism during testing restores the opiate conditioned place preference that is normally absent when D1 receptors are blocked only during training, suggesting that BLA D1 receptors can mediate state-dependent memory retrieval.
Amygdala; dopamine; state dependence; morphine; motivation; memory retrieval
Ongoing epidemiological studies estimate that greater than 60% of the adult US population may be categorized as either overweight or obese. There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and may result in increased risk for neurological co-morbidities like depressive illness. One potential mechanistic mediator linking obesity and depressive illness is the adipocyte derived hormone leptin. We previously demonstrated that lentivirus-mediated downregulation of hypothalamic insulin receptors increases body weight, adiposity and plasma leptin levels, which is consistent with features of the metabolic syndrome. Using this novel model of obesity, we examined performance in the forced swim test (FST), the sucrose preference test and the elevated plus maze (EPM), approaches that are often used as measures of depressive-like and anxiety-like behaviors, in rats that received third ventricular injections of either an insulin receptor antisense lentivirus (hypo-IRAS) or a control lentivirus (hypo-Con). Hypo-IRAS rats exhibited significant increases in immobility time and corresponding decreases in active behaviors in the FST and exhibited anhedonia as measured by decreased sucrose intake compared to hypo-Con rats. Hypo-IRAS rats also exhibited increases in anxiety-like behaviors in the EPM. Plasma, hippocampal and amygdalar brain-derived neurotrophic factor (BDNF) levels were reduced in hypo-IRAS rats, suggesting that the obesity/hyperleptinemic phenotype may elicit this behavioral phenotype through modulation of neurotrophic factor expression. Collectively, these data support the hypothesis for an increased risk for mood disorders in obesity, which may be related to decreased expression of hippocampal and amygdalar BDNF.
obesity; leptin; brain-derived neurotrophic factor; forced swim test; elevated plus maze; anhedonia
Inbred Wistar–Kyoto rats consistently display hypoactivity in tests of emotional behavior. We used them to test the hypothesis that the genetic factors underlying the behavioral decision-making process will vary in different environmental contexts. The contexts used were the open-field test (OFT), a novel environment with no explicit threats present, and the defensive-burying test (DB), a habituated environment into which a threat has been introduced. Rearing, a voluntary behavior was measured in both tests, and our study was the first to look for genetic loci affecting grooming, a relatively automatic, stress-responsive stereotyped behavior.
Quantitative trait locus analysis was performed on a population of 486 F2 animals bred from reciprocal intercrosses. The genetic architectures of DB and OFT rearing, and of DB and OFT grooming, were compared. There were no common loci affecting grooming behavior in both tests. These different contexts produced the stereotyped behavior via different pathways, and genetic factors seem to influence the decision-making pathways and not the expression of the behavior. Three loci were found that affected rearing behavior in both tests. However, in both contexts, other loci had greater effects on the behavior. Our results imply that environmental context’s effects on decision-making vary depending on the category of behavior.
Quantitative trait locus; Open-field test; Defensive burying; Rearing; Grooming; Context; Emotionality; Wistar–Kyoto
The Melanocortin system is involved in animal models of obesity and anorexia-cachexia and MC4 receptors (MC4-R) are currently a target system for the development of drugs aimed to treat obesity and eating disorders in humans. Previous evidence suggest that feeding peptides might lack their orexigenic activity while stimulate ethanol intake. The present study comparatively evaluated food intake (4-h interval) in Sprague-Dawley (SD) rats drinking ethanol (6% w/v, 2 bottle choice paradigm) (EE group) and ethanol-naïve (EN) rats in response to bilateral infusion of the selective MC4-R antagonist HS014 (0, 0.02 or 0.05 μg/0.5μl/site) or the selective MC4-R agonist cyclo(NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2 (0, 0.75 or 1.5 μg/0.5μl/site), into the lateral hypothalamus (LH), the nucleus accumbens (NAc), or the ventral tegmental area (VTA). The main findings in the study are: 1) LH-infusions of the MC4-R antagonist increased and the agonist reduced feeding and total calories consumed, while ethanol intake remained unaltered. 2) NAc- and VTA-infusions of the selective agonist reduced food, ethanol and total calories intake. 3) NAc- and VTA-infusions of the MC4-R antagonist increased feeding in EN rats, but not in EE animals which showed a mild increase in ethanol intake, while total calories consumed remained unaltered. Present data show that having ethanol available reduces feeding elicited by NAc and VTA-MC4-R blockade. Additionally, while MC4-R signalling in the LH appears to modulate homeostatic aspects of feeding, it may contribute to non-homeostatic aspects of ingestive behaviours in the VTA and the NAc.
feeding; ethanol; MC4 receptors; lateral hypothalamus; nucleus accumbens shell; ventral tegmental area
Extinguishing abnormally strengthened learned responses to cues associated with drugs of abuse remains a key tactic for alleviating addiction. To assist in developing pharmacotherapies to augment exposure therapy for relapse prevention, investigation into neurobiological underpinnings of drug-cue extinction learning is needed. We used regional analyses of c-Fos and GluR2 protein expression to delineate neural activity and plasticity that may be associated with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a light cue, and later underwent a single 2hr extinction session for which cocaine was withheld but response-contingent cues were presented (cocaine-cue extinction). Control groups consisted of rats yoked to animals self-administering cocaine and receiving saline non-contingently followed by an extinction session, or rats trained to self-administer cocaine followed by a no-extinction session for which levers were retracted, and cocaine and cues were withheld. Among 11 brain sites examined, extinction training increased c-Fos expression in basolateral amygdala and prelimbic prefrontal cortex of cocaine-cue extinguished rats relative to both control conditions. In dorsal subiculum and infralimbic prefrontal cortex, extinction training increased c-Fos expression in both cocaine-cue and saline-cue extinguished rats relative to the no-extinction control condition. GluR2 protein expression was not altered in any site examined after extinction or control training. Findings suggest that basolateral amygdala and prelimbic prefrontal cortex neurons are activated during acquisition of cocaine-cue extinction learning, a process that is independent of changes in GluR2 abundance. Other sites are implicated in processing the significance of cues that are present early in extinction training.
Basolateral amygdala; c-Fos protein; Cocaine; Extinction learning; GluR2 protein; Self-administration
Prenatal alcohol exposure (AE) is associated with cognitive and neurobehavioral abnormalities, such as increased motor activity and elevated anxiety, that may last a lifetime. Persistent sleep disruption may underlie these problems. Using a rat model, we investigated long-term alterations of sleep-wake behavior following AE during a critical early developmental period. Male rats received 2.6 g/kg of alcohol intragastrically twice daily on postnatal days (PD) 4-9, a developmental period equivalent to the third trimester of human pregnancy (AE group), or were sham-intubated (S group). On PD52-80, they were instrumented for tethered electroencephalogram and nuchal electromyogram recording and habituated to the recording procedures. Sleep-wake behavior was then recorded during one 24 h-long session. Wake, slow-wave sleep (SWS) and rapid eye movement sleep (REMS) were scored in 10 s epochs during 6 h of the lights-on (rest) and 6 h of the lights-off (active) periods. During the active period, REMS percentage was significantly lower (4.7±0.9 (SE) vs. 8.2±0.9; p<0.02) and the percentage of SWS tended to be lower (p=0.07) in AE than S rats (N=6/group). During the rest period, sleep and wake amounts did not differ between the groups, but AE rats had longer latency to both SWS and REMS onset (p=0.02 and 0.003, respectively). Our data demonstrate that, in a rat model of prenatal AE, impaired sleep-wake behavior persists into the adulthood. Disordered sleep may exacerbate cognitive and behavioral disorders seen in human victims of prenatal AE.
development; fetal alcohol spectrum disorders; GABA; hypothalamus; sleep
In the present study, we determined the effects of environmental enrichment (EE; Kong Toys® and Nestlets®) on sexually diergic HPA axis responses to single-dose nicotine (NIC), single-dose NIC following continuous NIC administration for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) in male and female rats. Blood sampling occurred before and after MEC and NIC administrations for the determination of adrenocorticotropic hormone (ACTH) and corticosterone (CORT).
Supporting and extending our previous findings, EE appeared to produce anxiolytic effects by reducing hormone responses: Male and female rats housed with EE had lower baseline ACTH and significantly lower HPA axis responses to the mild stress of saline (SAL) injection than did those housed without EE. The sexually diergic responses to single dose NIC, continuous NIC, and MEC-induced NIC withdrawal were reduced by EE in many male and female groups. ACTH responses to continuous NIC and MEC-induced NIC withdrawal were blunted to a greater extent in female EE groups than in male EE groups, suggesting that females are more sensitive to the anxiolytic effects of EE. Because EE lowered stress-responsive hormones of the HPA axis in most groups, EE may be a useful intervention for stress reduction in animal models of NIC addiction. As well, the effectiveness of EE in animal studies of NIC withdrawal may enlighten human studies addressing coping styles and tobacco cessation in men and women.
Environmental enrichment; HPA Axis; Mecamylamine; Nicotine; Sexual Diergism; Withdrawal
Classical behavioral tests in animal models of trigeminal neuropathic pain measure reflexive responses that are not necessarily measures of pain. To overcome the problem, we created a chronic constrictive nerve injury rat model of pain (CCI) by ligation of the infraorbital nerve (ION), and applied the orofacial operant test to assess behavioral responses to mechanical and cold stimulation in these rats. Animals were trained to voluntarily contact their facial region to a mechanical or a cold stimulation module in order to access sweetened milk as a positive reward. ION-CCI rats displayed aversive behaviors to innocuous mechanical stimuli, as indicated by a significant decrease in both contact time and the numbers of long contact events in comparison with sham group. For cold stimulation, ION-CCI rats displayed aversive behaviors to both innocuous (17 °C) and noxious cold temperatures (12 °C and 5 °C), as indicated by a significant decrease in both contact time and the numbers of long contact events at the cooling temperatures. The decreases of the contact time and numbers in ION-CCI rats were partially abolished by morphine. Our orofacial operant test demonstrates mechanical allodynia, cold allodynia, and hyperalgesia in rats with chronic trigeminal nerve injury. The neuropathic pain in ION-CCI rats was partially alleviated by morphine. Thus, orofacial operant test provides a desirable behavioral assessment method for preclinical studies of chronic trigeminal neuropathic pain.
Trigeminal neuropathic pain; Mechanical allodynia; Cold allodynia; Behavioral assessment; Operant behavior
► Infants preferentially orient to socially relevant information such as faces. ► Infants at-risk for autism have a tendency to sustain attention to faces. ► Those infants who later develop autism show an equally strong face orienting response. ► Combined influence of social and attentional brain systems is implicated in autism.
A popular idea related to early brain development in autism is that a lack of attention to, or interest in, social stimuli early in life interferes with the emergence of social brain networks mediating the typical development of socio-communicative skills. Compelling as it is, this developmental account has proved difficult to verify empirically because autism is typically diagnosed in toddlerhood, after this process of brain specialization is well underway. Using a prospective study, we directly tested the integrity of social orienting mechanisms in infants at-risk for autism by virtue of having an older diagnosed sibling. Contrary to previous accounts, infants who later develop autism exhibit a clear orienting response to faces that are embedded within an array of distractors. Nevertheless, infants at-risk for autism as a group, and irrespective of their subsequent outcomes, had a greater tendency to select and sustain attention to faces. This pattern suggests that interactions among multiple social and attentional brain systems over the first two years give rise to variable pathways in infants at-risk.
Autism; Infancy; At-risk; Face-processing; Attention; Prospective study
► Deletion of Syn isoforms widely impairs social behavior. ► SynII−/− mice display impaired social interaction, novelty and recognition. ► SynI−/− and SynII−/− mice are characterized by increased social dominance. ► Young and adult SynI−/− and SynIII−/− mice exhibit deficits in social transmission of food preference. ► Social deficits in SynI−/− and SynII−/− mice appear before the onset of epilepsy.
Several synaptic genes predisposing to autism-spectrum disorder (ASD) have been identified. Nonsense and missense mutations in the SYN1 gene encoding for Synapsin I have been identified in families segregating for idiopathic epilepsy and ASD and genetic mapping analyses have identified variations in the SYN2 gene as significantly contributing to epilepsy predisposition. Synapsins (Syn I/II/III) are a multigene family of synaptic vesicle-associated phosphoproteins playing multiple roles in synaptic development, transmission and plasticity. Lack of SynI and/or SynII triggers a strong epileptic phenotype in mice associated with mild cognitive impairments that are also present in the non-epileptic SynIII−/− mice. SynII−/− and SynIII−/− mice also display schizophrenia-like traits, suggesting that Syns could be involved in the regulation of social behavior. Here, we studied social interaction and novelty, social recognition and social dominance, social transmission of food preference and social memory in groups of male SynI−/−, SynII−/− and SynIII−/− mice before and after the appearance of the epileptic phenotype and compared their performances with control mice. We found that deletion of Syn isoforms widely impairs social behaviors and repetitive behaviors, resulting in ASD-related phenotypes. SynI or SynIII deletion altered social behavior, whereas SynII deletion extensively impaired various aspects of social behavior and memory, altered exploration of a novel environment and increased self-grooming. Social impairments of SynI−/− and SynII−/− mice were evident also before the onset of seizures. The results demonstrate an involvement of Syns in generation of the behavioral traits of ASD and identify Syn knockout mice as a useful experimental model of ASD and epilepsy.
Autism spectrum disorder; Social behavior; Synaptopathies; Synaptic vesicles; Epilepsy
Systemic administration of dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC) antagonists blocked both acquisition and expression of fructose-conditioned flavor preferences (CFP). It is unclear what brain circuits are involved in mediating these effects. The present study investigated DA signaling within the nucleus accumbens shell (NAcS), amygdala (AMY) and medial prefrontal cortex (mPFC) in the acquisition and expression of fructose-CFP. In Experiment 1, separate groups of rats were injected daily in the NAcS or AMY with saline, SCH (24 nmol) or RAC (24 nmol) prior to training sessions with a flavor (CS+) mixed with 8% fructose and 0.2% saccharin (CS+/F) and a different flavor (CS−) mixed with only 0.2% saccharin. In the two-bottle choice tests with 0.2% saccharin, only rats injected with RAC in the AMY failed to acquire a CS+ preference (45–54%). In Experiment 2, new rats were identically trained, but saline, SCH and RAC were injected in the mPFC. In subsequent two-bottle choice tests, SCH- and RAC-treated rats failed to exhibit a CS+ preference (50–56%). In Experiment 3, new rats were trained with CS+/F and CS− without injections. Subsequent two-bottle choice tests were then conducted following bilateral injections of SCH or RAC in the mPFC at total doses of 0, 12, 24 and 48 nmol. Expression of the CS+ preference failed to be affected by either antagonist, indicating that the mPFC is not involved in the maintenance of this preference. These data indicate that the acquisition of fructose-CFP is dependent on DA signaling in the mPFC and AMY.
Flavor-flavor learning; Sweet taste; Saccharin; SCH23390; Raclopride; Nucleus accumbens shell
Aside from the well-known influence of serotonin (5-hydroxytryptamine, 5-HT) on emotional regulation, more recent investigations have revealed the importance of this monoamine in modulating cognition. Parachlorophenylalanine (PCPA) depletes 5-HT by inhibiting tryptophan hydroxylase, the enzyme required for 5-HT synthesis and, if administered at sufficiently high doses, can result in a depletion of at least 90% of the brain s 5-HT levels. The present study assessed the long-lasting effects of widespread 5-HT depletions on two tasks of cognitive flexibility in Long Evans rats: effort discounting and reversal learning. We assessed performance on these tasks after administration of either 250 or 500 mg/kg PCPA or saline (SAL) on two consecutive days. Consistent with a previous report investigating the role of 5-HT on effort discounting, pretreatment with either dose of PCPA resulted in normal effortful choice: All rats continued to climb tall barriers to obtain large rewards and were not work-averse. Additionally, rats receiving the lower dose of PCPA displayed normal reversal learning. However, despite intact motivation to work for food rewards, rats receiving the largest dose of PCPA were unexpectedly impaired relative to SAL rats on the pretraining stages leading up to reversal learning, ultimately failing to approach and respond to the stimuli associated with reward. High performance liquid chromatography (HPLC) with electrochemical detection confirmed 5-HT, and not dopamine, levels in the ventromedial frontal cortex were correlated with this measure of associative reward learning.
Effort discounting; reversal learning; ventromedial frontal cortex; HPLC
Photoperiodism is a biological phenomenonin which environmental day length is monitored to ascertain time of year to engage in seasonally-appropriate adaptations. This trait is common among organisms living outside of the tropics. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive responses to short day lengths, including reduced hippocampal volume, impairments in hippocampal-mediated memory, and enhanced hypothalamic-pituitary-adrenal axis reactivity. Because these photoperiodic changes in brain and behavior mirror some of the etiology of post-traumatic stress disorder (PTSD), we hypothesized that photoperiod may also alter fear memory and neuronal morphology within the hippocampus - basolateral amygdala - prefrontal cortex fear circuit. Ten weeks of exposure to short days increased fear memory in an auditory-cued fear conditioning test. Short days also increased dendritic spine density of the neurons of the basolateral amygdala, without affecting morphology of pyramidal neurons within the infralimbic region of the medial prefrontal cortex. Taken together, photoperiodic phenotypic changes in brain morphology and physiology induced by a single environmental factor, exposure to short day lengths, affect responses to fearful stimuli in white-footed mice. These results have potential implications understanding seasonal changes in fear responsiveness, as well as for expanding translational animal models for studying gene-environment interactions underlying psychiatric diseases, such as PTSD.
PTSD; BLA; spine density; auditory fear conditioning; predator avoidance
Humans who exercise are less likely to suffer from stress-related mood disorders. Similarly, rats allowed voluntary access to running wheels have constrained corticosterone responses to mild stressors and are protected against several behavioral consequences of uncontrollable stress which resemble symptoms of human anxiety and depression, including exaggerated fear and deficits in shuttle box escape learning. Although exercise conveys clear stress resistance, the duration of time the protective effects of exercise against the behavioral consequences of uncontrollable stress persist following exercise cessation is unknown. The current studies investigated 1) whether exercise-induced stress resistance extends to social avoidance, another anxiety-like behavior elicited by uncontrollable stressor exposure, and 2) the duration of time the protective effects of exercise persist following forced cessation of exercise. Six weeks of wheel running constrained the increase in corticosterone elicited by social exploration testing, and prevented the reduction in social exploration, exaggerated shock-elicited fear, and deficits in escape learning produced by uncontrollable stress. The protective effect of voluntary exercise against stress-induced interference with escape learning persisted for 15 days, but was lost by 25 days, following cessation of exercise. An anxiogenic effect, as revealed by a reduction in social exploration and an increase in fear behavior immerged as a function of time following cessation of exercise. Results demonstrate that the protective effect of voluntary exercise against the behavioral consequences of uncontrollable stress extends to include social avoidance, and can persist for several days following exercise cessation despite an increase in anxiety produced by forced cessation of exercise.
wheel running; depression; anxiety; learned helplessness; serotonin; social exploration
Approximately 80% of smokers initiate tobacco use during adolescence, suggesting that nicotine initiation and nicotine dependence have a substantial age component. There also is a substantial genetic influence on smoking behaviors such as age of initiation and the development of nicotine dependence. The goal of this study was to examine both genetic background and age dependent effects on oral nicotine self-administration and anxiety-like behaviors in mice. Two inbred mouse strains (C3H/Ibg and C57BL/6J) were assessed for oral nicotine preference during early adolescence (postnatal day 24–35), middle adolescence (postnatal day 36–47), late adolescence (postnatal day 48–59), adulthood (postnatal day 60+) and 2 months following their initial exposure to nicotine. Mice also were assessed for innate anxiety using an elevated zero maze to determine if age and/or genetic background influenced anxiety-like behaviors. Results indicated that initial nicotine preference and nicotine preference two months after an initial exposure are both strain and age dependent. Age also had an effect on some baseline anxiety measures but strain differences for most zero maze measures were present throughout all age groups. In general, early adolescent C3H mice exhibited greater nicotine preference while C57 mice displayed greater preference during middle adolescence and upon a second exposure to nicotine. In contrast, C57 mice exhibited reduced anxiety across all ages tested. These studies indicate that genetic background should be considered when evaluating age-dependent effects of drugs of abuse and baseline anxiety-like behaviors.
Mouse; Strain; Nicotine; Adolescent; Anxiety; Nicotine Preference
The zebrafish may be an ideal tool with which genes underlying learning and memory can be identified and functionally investigated. From a translational viewpoint, relational learning and episodic memory are particularly important as their impairment is the hallmark of prevalent human neurodegenerative diseases. Recent reports suggest that zebrafish are capable of solving complex relational-type associative learning tasks, namely spatial learning tasks. However, it is not known whether good performance in these tasks was truly based upon relational learning or upon a single CS-US association. Here we study whether zebrafish can find a rewarding stimulus (sight of conspecifics) based upon a single associative cue or/and upon the location of the reward using a method conceptually similar to ‘context and cue dependent fear conditioning’ employed with rodents. Our results confirm that zebrafish can form an association between a salient visual cue and the rewarding stimulus and at the same time they can also learn where the reward is presented. Although our results do not prove that zebrafish form a dynamic spatial map of their surroundings and use this map to locate their reward, they do show that these fish perform similarly to rodents whose hippocampal function is unimpaired. These results further strengthen the notion that complex cognitive abilities exist in the zebrafish and thus they may be analyzed using the excellent genetic tool set developed for this simple vertebrate.
Zebrafish; spatial learning; relational learning; associative learning; social behavior
This experiment examined the effects on memory of interactions of cycloheximide dose and training foot shock intensity. Mice received injections of cycloheximide (120 mg/kg, s.c.) or saline 30 min prior to inhibitory avoidance training with shock intensities of 100, 150, 250 or 300 µA (1 sec duration). Memory was tested 48 hr later. The saline control mice showed increasing memory latencies as a function of shock intensity. The ability of cycloheximide to impair memory increased as the training shock intensity increased. In a second experiment, mice were trained with a 200 µA (1 sec duration) shock and received injections of saline or cycloheximide at one of several doses (30, 60 or 120 mg/kg). Under these training conditions, cycloheximide enhanced memory in an inverted-U dose-response manner. These findings are consistent with prior findings suggesting that protein synthesis inhibitors act on memory by altering modulators of memory formation as a secondary consequence of the inhibition of protein synthesis rather than by interfering with training-initiated synthesis of proteins required for memory formation.
cycloheximide; protein synthesis; memory enhancement; long-term memory; consolidation; inhibitory avoidance
In rodents, exercise increases hippocampal neurogenesis and allows for better learning and memory performance on water maze tasks. While exercise has also been shown to be beneficial for the brain and behavior in humans, no study has examined how exercise impacts spatial learning using a directly translational water maze task, or if these relationships exist during adolescence – a developmental period which the animal literature has shown to be especially vulnerable to exercise effects. In this study, we investigated the influence of aerobic fitness on hippocampal size and subsequent learning and memory, including visuospatial memory using a human analogue of the Morris Water Task, in 34 adolescents. Results showed that higher aerobic fitness predicted better learning on the virtual Morris Water Task and larger hippocampal volumes. No relationship between virtual Morris Water Task memory recall and aerobic fitness was detected. Aerobic fitness, however, did not relate to global brain volume, or verbal learning, which might suggest some specificity of the influence of aerobic fitness on the adolescent brain. This study provides a direct translational approach to the existing animal literature on exercise, as well as adds to the sparse research that exists on how aerobic exercise impacts the developing human brain and memory.
exercise; adolescence; neuroimaging; spatial memory; hippocampus
In this study we transplanted bone marrow mononuclear cells (BM-MNCs) or microglia into rats that had undergone permanent cerebral ischemia and observed the distribution or morphology of transplanted cells in vivo. In addition, we also compared the effects of BM-MNCs and microglia on infarct volume, brain water content, and functional outcome after permanent cerebral ischemia. BM-MNCs and microglia were obtained from femur and brain, respectively, of newborn rats. Adult rats were injected with vehicle or 3 million BM-MNCs or microglia via the tail vein 24 h after permanent middle cerebral artery occlusion (pMCAO). The distribution or morphologic characteristics of transplanted BM-MNCs (BrdU/double-stained CD34 and CD45) and microglia (BrdU/double-stained Iba-1) were detected with immunofluorescent staining at 3 or 7 and 14 days after pMCAO. Functional deficits were assessed by the modified neurologic severity score at 1, 3, 7 and 14 days after pMCAO. Brain water content was assessed with dry–wet weight method at 3 days, and infarct volume was determined with 2,3,5-triphenyltetrazolium chloride (TTC) staining at 14 days. More BrdU/double-stained CD45- and Iba-1-positive cells were observed than BrdU/double-stained CD34-positive cells around the infarcted area. Some infused microglia show the morphology of innate microglia at 7 days and the increased numbers can be detected at 14 days after pMCAO. BM-MNC-treated rats showed a significant reduction in infarct volume and brain water content compared to vehicle- and microglia-treated rats. In addition, BM-MNC treatment reduced neurologic deficit scores compared to those in the other groups. The results provide evidence that infusion of BM-MNC, but not microglia, is neuroprotective after permanent cerebral ischemia.
Bone marrow mononuclear cells; Cerebral ischemia; Microglia; Therapeutic effect