Hippocampal-lesioned Rats Research Articles

Memory deficits and hippocampal cytokine expression in a rat model of ADHD

Attention-deficit/hyperactivity disorder (ADHD) is a complex behavioral disorder characterized by hyperactivity, impulsivity, inattention, and deficits in working memory and time perception. While animal models have advanced our neurobiological understanding of this condition, there are limited and inconsistent data on working and elapsed time memory function. Inflammatory signaling has been identified as a key factor in memory and cognitive impairments, but its role in ADHD remains unclear. Additionally, the disproportionate investigation of male subjects in ADHD research has contributed to a poor understanding of the disorder in females. This study sought to investigate the potential connections between memory, neuroimmunology, and ADHD in both male and female animals. Specifically, we utilized the spontaneously hypertensive rat (SHR), one of the most extensively studied animal models of ADHD. Compared to their control, the Wistar-Kyoto (WKY) rat, male SHR are reported to exhibit several behavioral phenotypes associated with ADHD, including hyperactivity, impulsivity, and poor sustained attention, along with impairments in learning and memory. As the hippocampus is a key brain region for learning and memory, we examined the behavior of male and female SHR and WKY rats in two hippocampal-dependent memory tasks. Our findings revealed that SHR have delay-dependent working memory deficits that were similar to, albeit less severe than, those seen in hippocampal-lesioned rats. We also observed impairments in elapsed time processing in female SHR, particularly in the discrimination of longer time durations. To investigate the impact of inflammatory signaling on memory in these rats, we analyzed the levels of several cytokines in the dorsal and ventral hippocampus of SHR and WKY. Although we found some sex and genotype differences, concentrations were generally similar between groups. Taken together, our results indicate that SHR exhibit deficits in spatial working memory and memory for elapsed time, as well as some differences in hippocampal cytokine concentrations. These findings contribute to a better understanding of the neurobiological basis of ADHD in both sexes and may inform future research aimed at developing effective treatments for the disorder. Nonetheless, the potential mediating role of neuroinflammation in the memory symptomatology of SHR requires further investigation.

Alterations in prefrontal cortical neuregulin-1 levels in post-pubertal rats with neonatal ventral hippocampal lesions.

Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the N-methyl-D-aspartate receptor and the GABAA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.

Cannabis Vapor Exposure Alters Neural Circuit Oscillatory Activity in a Neurodevelopmental Model of Schizophrenia: Exploring the Differential Impact of Cannabis Constituents.

Cannabis use is highly prevalent in patients with schizophrenia and worsens the course of the disorder. To understand how exposure to cannabis changes schizophrenia-related oscillatory disruptions, we investigated the impact of administering cannabis vapor containing either Δ9-tetrahydrocannabinol (THC) or balanced THC/cannabidiol (CBD) on oscillatory activity in the neonatal ventral hippocampal lesion (NVHL) rat model of schizophrenia. Male Sprague Dawley rats underwent lesion or sham surgeries on postnatal day 7. In adulthood, electrodes were implanted targeting the cingulate cortex (Cg), the prelimbic cortex (PrLC), the hippocampus (HIP), and the nucleus accumbens (NAc). Local field potential recordings were obtained after rats were administered either the “THC-only” cannabis vapor (8–18% THC/0% CBD) or the “Balanced THC:CBD” cannabis vapor (4–11% THC/8.5–15.5% CBD) in a cross-over design with a 2-week wash-out period between exposures. Compared to controls, NVHL rats had reduced baseline gamma power in the Cg, HIP, and NAc, and reduced HIP-Cg high-gamma coherence. THC-only vapor exposure broadly suppressed oscillatory power and coherence, even beyond the baseline reductions observed in NHVL rats. Balanced THC:CBD vapor, however, did not suppress oscillatory power and coherence, and in some instances enhanced power. For NVHL rats, THC-only vapor normalized the baseline HIP-Cg high-gamma coherence deficits. NHVL rats demonstrated a 20 ms delay in HIP theta to high-gamma phase coupling, which was not apparent in the PrLC and NAc after both exposures. In conclusion, cannabis vapor exposure has varying impacts on oscillatory activity in NVHL rats, and the relative composition of naturally occurring cannabinoids may contribute to this variability.

The Impact of Adolescent Alcohol Exposure on Nicotine Behavioral Sensitization in the Adult Male Neonatal Ventral Hippocampal Lesion Rat.

Nicotine and alcohol use is highly prevalent among patients with serious mental illness, including those with schizophrenia (SCZ), and this co-occurrence can lead to a worsening of medical and psychiatric morbidity. While the mechanistic drivers of co-occurring SCZ, nicotine use and alcohol use are unknown, emerging evidence suggests that the use of drugs during adolescence may increase the probability of developing psychiatric disorders. The current study used the neonatal ventral hippocampal lesion (NVHL) rat model of SCZ, which has previously been shown to have enhanced nicotine behavioral sensitization and, following adolescent alcohol, increased alcohol consumption. Given how commonly alcohol is used by adolescents that develop SCZ, we used the NVHL rat to determine how exposure to adolescent alcohol impacts the development of nicotine behavioral sensitization in adulthood. Male Sprague-Dawley rats underwent the NVHL surgery or a sham (control) surgery and subsequently, half of each group was allowed to drink alcohol during adolescence. Nicotine behavioral sensitization was assessed in adulthood with rats receiving subcutaneous injections of nicotine (0.5 mg/kg) each day for 3 weeks followed by a nicotine challenge session 2 weeks later. We demonstrate that all groups of rats became sensitized to nicotine and there were no NVHL-specific increases in nicotine behavioral sensitization. We also found that NVHL rats appeared to develop sensitization to the nicotine paired context and that adolescent alcohol exposure blocked this context sensitization. The current findings suggest that exposure to alcohol during adolescence can influence behaviors that manifest in the adult NVHL rat (i.e., context sensitization). Interestingly, nicotine behavioral sensitization levels were not altered in the NVHL groups regardless of adolescent alcohol exposure in contrast to prior reports.

Spatial working memory in rats: Crucial role of the hippocampus in the allothetic place avoidance alternation task demanding stimuli segregation

Working memory is a construct that contains goal maintenance, interference control and memory capacity domains. Spatial working memory in presence of conflicting stimuli requires segregation and maintenance of the relevant information about a goal over a short period of time. Besides the prefrontal cortex, the hippocampus is an anatomical substrate for the working memory. We hypothesized that in a highly challenging task, where spatial stimuli are in a conflict and only some of them describe the goal location, the spatial working memory will be strongly dependant on the hippocampus. To verify this, we used an allothetic place avoidance alternation task (APAAT). Performance of this task demands a small number of entries and a long maximum time avoided between consecutive entries to the shock sector. These parameters reflected both domains of working memory. The experiment was conducted on hippocampal lesioned (HIPP n = 12) and sham-operated (CTRL n = 8) rats trained in four APAAT days, each consisting of four 5-minute stages: habituation, stage1 (st1) and stage2 (st2) of memory training, a 5-minute break followed by a retrieval test. The position of the shock sector was changed each day. The HIPP rats were impaired on both stages of memory training, whereas CTRL rats presented significant memory improvement on stage2. In HIPP rats the cognitive skill learning measured as shock per entrance ratio was compromised. Hippocampal lesions did not impair locomotor activity. In summary, even slight bilateral damage to the hippocampus is blocking working memory formation in a difficult task.

In the temporal organization of episodic memory, the hippocampus supports the experience of elapsed time.

Space and time are both essential features of episodic memory, for which the hippocampus is critical (Howard & Eichenbaum, 2015). Spatial tasks have been used effectively to study the behavioral relevance of place cells. However, the behavioral paradigms utilized for the study of time cells have not used time duration as a variable that animals need to be aware of to solve the task. Therefore, the behavioral relevance of this cell firing is unclear. In order to directly study the role of the hippocampus in processing elapsed time, we created a novel time duration discrimination task. Rats learned to make a decision to turn left or right depending on the preceding tone duration (10 s, left turn; 20 s, right turn). Once the rats reached criterion performance of 90% correct on two out of three consecutive days, they received either an excitotoxic hippocampal lesion or a sham-lesion surgery. After recovery, rats were tested to determine hippocampal involvement in discriminating time duration. Rats with hippocampal lesions performed at chance level on their first testing day postlesion, and they were impaired relative to the sham-lesioned rats. Although the hippocampal-lesioned rats began discriminating at above chance level, their performance never returned to criterion even with 50 days of postoperative testing. Furthermore, while sham rats showed no difference in the number of errors they made on 10- versus 20-s delay trials, hippocampal lesion rats similarly improved their performance under the 10-s delay condition, but not under the 20-s delay condition. Results indicate that hippocampal lesions resulted in a selective impairment in discriminating elapsed time only during the longer delay trials. The implications of these results are discussed in relation to the limits of working-memory capacity and to the role of sustained hippocampal time cell activity in memory performance depending on the perceived relevance of the delay period.

Role of prefrontal cortical 5-HT2A receptors and serotonin transporter in the behavioral deficits in post-pubertal rats following neonatal lesion of the ventral hippocampus

Neonatal ventral hippocampal-lesioned (NVHL) rats have been shown to display neurochemical and behavioral abnormalities at adulthood, analogous to some of those seen in schizophrenia. Serotonergic neurotransmission is implicated the pathophysiology and treatment of schizophrenia. In this study, we evaluated possible role of serotonergic transmission is the behaviors of NVHL-lesioned rats. Bilateral lesions to the ventral hippocampus (VH) in rat pups were made using the excitotoxin ibotenic acid. We investigated 5-HT2A-receptor and SERT binding sites in cortical and subcortical areas in post-pubertal NVHL and sham-lesioned rats, using quantitative receptor autoradiography. We compared a 5-HT-dependent behavior in NVHL and sham animals, the wet-dog shake response (WDSr) to a 5-HT2A receptor agonist DOI. In addition, we studied prepulse inhibition (PPI) of startle responses in NVHL and Sham-lesioned animals treated with antipsychotic drugs haloperidol, risperidone and clozapine and 5-HT2A antagonists ketanserin or MDL100907. The WDSr elicited by DOI was enhanced in post-pubertal NVHL rats compared to sham-lesioned controls. Moreover, post-pubertal NVHL rats exhibited PPI deficits which was reversed by atypical antipsychotics, ketanserin and MDL100907. A significant increase in 5-HT2A-like receptor binding was observed in the medial prefrontal cortex (mPFC) in post-pubertal NVHL rats without any significant change in the striatum and ventral pallidum. A significant increase in SERT-like binding was also observed in the mPFC and striatum of NVHL rats at pre-pubertal period; however, at post-pubertal age, the binding remained elevated in mPFC only. These data suggest that increased prefrontal cortical 5-HT transmission may play a role in the behavioral deficits observed in this neurodevelopmental model of schizophrenia.

En route to delineating hippocampal roles in spatial learning

The precise role played by the hippocampus in spatial learning tasks, such as the Morris Water Maze (MWM), is not fully understood. One theory is that the hippocampus is not required for ‘knowing where’ but rather is crucial in ‘getting there’. To explore this idea in the MWM, we manipulated ‘getting there’ variables, such as passive transport or active swimming towards the hidden platform, in rats with and without hippocampal lesions.Our results suggested that for intact rats, self-motion cues enroute to the hidden goal were a necessary component for ‘place learning’ to progress. Specifically, intact rats could not learn the hidden goal location, when passively transported to it, despite extensive training. However, when rats were either given hippocampal lesions, or placed in a light-tight box during transportation to the hidden goal, passive-placement spatial learning was facilitated. In a subsequent experiment, the ‘getting there’ component of place navigation was simplified, via the placement of two overhead landmarks, one of which served as a beacon. When ‘getting there’ was made easier in this way, hippocampal lesions did not induce deficits in ‘knowing where’ the goal was. In fact, similar to the facilitation observed in passive-placement spatial learning, hippocampal lesions improved landmark learning relative to controls. Finally, demonstrating that our lesions were sufficiently deleterious, hippocampal-lesioned rats were impaired, as predicted, in an environmental-boundary based learning task. We interpret these results in terms of competition between multiple memory systems, and the importance of self-generated motion cues in hippocampal spatial mapping.

Polysubstance addiction vulnerability in mental illness: Concurrent alcohol and nicotine self-administration in the neurodevelopmental hippocampal lesion rat model of schizophrenia.

Multiple addictions frequently occur in patients with mental illness. However, basic research on the brain-based linkages between these comorbidities is extremely limited. Toward characterizing the first animal modeling of polysubstance use and addiction vulnerability in schizophrenia, adolescent rats with neonatal ventral hippocampal lesions (NVHLs) and controls had 19 weekdays of 1hour/day free access to alcohol/sucrose solutions (fading from 10% sucrose to 10% alcohol/2% sucrose on day 10) during postnatal days (PD 35-60). Starting in adulthood (PD 63), rats acquired lever pressing for concurrent oral alcohol (10% with 2% sucrose) and iv nicotine (0.015mg/kg/injection) across 15 sessions. Subsequently, 10 operant extinction sessions and 3 reinstatement sessions examined drug seeking upon withholding of nicotine, then both nicotine and alcohol, then reintroduction. Adolescent alcohol consumption did not differ between NVHLs and controls. However, in adulthood, NVHLs showed increased lever pressing at alcohol and nicotine levers that progressed more strongly at the nicotine lever, even as most pressing by both groups was at the alcohol lever. In extinction, both groups showed expected declines in effort as drugs were withheld, but NVHLs persisted with greater pressing at both alcohol and nicotine levers. In reinstatement, alcohol reaccess increased pressing, with NVHLs showing greater nicotine lever activity overall. Developmental temporal-limbic abnormalities that produce mental illness can thus generate adult polydrug addiction vulnerability as a mechanism independent from putative cross-sensitization effects between addictive drugs. Further preclinical modeling of third-order (and higher) addiction-mental illness comorbidities may advance our understanding and treatment of these complex, yet common brain illnesses.

Salvia officinalis induces antidepressant-like effect, anxiolytic activity and learning improvement in hippocampal lesioned and intact adult rats.

The anxiolytic and antidepressant like effects of Salvia officinalis extract (50, 100 and 200 mg/kg) were evaluated using marble burying, forced swimming and open-field tests in intact and hippocampal lesioned rats. Additionally, S. officinalis was evaluated on rat's memory using conditioned learning test. and we screened the methanolic extract for anti-oxidant activity, phytochemical and high performance liquid chromatography analyses. The administration of sage extract showed a significant reduction of immobility time in lesioned and intact animals during the forced swim test and anxiolytic effect in marble burying test. In the case of conditioned learning paradigm, memory enhancement was observed in sage treated group which indicates a cognition improvement. These activities seem to be related to the anti-oxidant capacity and the phytochemicals (phenolic, flavonoid, and tannin) detected into the extract of S. officinalis. The findings show that the methanolic extract of sage possess antidepressant-like effect, anxiolytic activity and also may contain bioactive compounds that stimulate learning in rat.

Auditory steady-state responses in primary and non-primary regions of the auditory cortex in neonatal ventral hippocampal lesion rats.

Auditory steady-state responses (ASSRs) represent the electrophysiological activity of the auditory nervous system in response to a periodic acoustic stimulus. Spectrogram analysis can reveal the frequency and phase information entrained in ASSRs. Clinically, the ASSR is used to detect abnormalities in electroencephalographs obtained from schizophrenia patients, who show reduced power and phase locking of ASSRs. The neonatal ventral hippocampal lesion (NVHL) rat is a widely used model to investigate the neurodevelopmental mechanisms of schizophrenia. It has been established that NVHL rats exhibit several schizophrenia-like behavioral and molecular abnormalities. However, no clear abnormalities in ASSRs have been reported to date. The present study compared ASSRs of adult NVHL and sham-operated rats. We inserted microelectrodes into the primary auditory cortex (A1) or posterior auditory field (PAF) and recorded the local field potential (LFP) in response to 40- and 80-Hz click train stimuli. Spectrogram analysis was performed to obtain the mean trial power (MTP) and phase-locking factor (PLF) of the click train-evoked LFPs. We found that in the control animals, A1 showed a stronger MTP and PLF of ASSR than PAF, and NVHL operation mainly impaired the ASSR in PAF. Analysis of spike activity also indicated that NVHL operation extended the duration of tone-evoked responses in PAF neurons. Our results reveal, for the first time, that NVHL may distinctly influence the neural activities of primary and non-primary fields of the auditory cortex.

Utilizing the Modified T-Maze to Assess Functional Memory Outcomes After Cardiac Arrest

Background: Evaluating mild to moderate cognitive impairment in a global cerebral ischemia (i.e. cardiac arrest) model can be difficult due to poor locomotion after surgery. For example, rats who undergo surgical procedures and are subjected to the Morris water maze may not be able to swim, thus voiding the experiment. New Method: We established a modified behavioral spontaneous alternation T-maze test. The major advantage of the modified T-maze protocol is its relatively simple design that is powerful enough to assess functional learning/memory after ischemia. Additionally, the data analysis is simple and straightforward. We used the T-maze to determine the rats' learning/memory deficits both in the presence or absence of mild to moderate (6 min) asphyxial cardiac arrest (ACA). Rats have a natural tendency for exploration and will explore the alternate arms in the T-maze, whereas hippocampal-lesioned rats tend to adopt a side-preference resulting in decreased spontaneous alternation ratios, revealing the hippocampal-related functional learning/memory in the presence or absence of ACA. Results: ACA groups have higher side-preference ratios and lower alternations as compared to control. Comparison with Existing Method(s): The Morris water and Barnes maze are more prominent for assessing learning/memory function. However, the Morris water maze is more stressful than other mazes. The Barnes maze is widely used to measure reference (long-term) memory, while ACA-induced neurocognitive deficits are more closely related to working (short-term) memory. Conclusions: We have developed a simple, yet effective strategy to delineate working (short-term) memory via the T-maze in our global cerebral ischemia model (ACA).

Utilizing the Modified T-Maze to Assess Functional Memory Outcomes After Cardiac Arrest.

Evaluating mild to moderate cognitive impairment in a global cerebral ischemia (i.e. cardiac arrest) model can be difficult due to poor locomotion after surgery. For example, rats who undergo surgical procedures and are subjected to the Morris water maze may not be able to swim, thus voiding the experiment. New Method: We established a modified behavioral spontaneous alternation T-maze test. The major advantage of the modified T-maze protocol is its relatively simple design that is powerful enough to assess functional learning/memory after ischemia. Additionally, the data analysis is simple and straightforward. We used the T-maze to determine the rats' learning/memory deficits both in the presence or absence of mild to moderate (6 min) asphyxial cardiac arrest (ACA). Rats have a natural tendency for exploration and will explore the alternate arms in the T-maze, whereas hippocampal-lesioned rats tend to adopt a side-preference resulting in decreased spontaneous alternation ratios, revealing the hippocampal-related functional learning/memory in the presence or absence of ACA. ACA groups have higher side-preference ratios and lower alternations as compared to control. Comparison with Existing Method(s): The Morris water and Barnes maze are more prominent for assessing learning/memory function. However, the Morris water maze is more stressful than other mazes. The Barnes maze is widely used to measure reference (long-term) memory, while ACA-induced neurocognitive deficits are more closely related to working (short-term) memory. We have developed a simple, yet effective strategy to delineate working (short-term) memory via the T-maze in our global cerebral ischemia model (ACA).

Rodent models of genetic and chromosomal variations in psychiatric disorders.

Elucidating the molecular basis of complex human psychiatric disorders is challenging due to the multitude of factors that underpin these disorders. Genetic and chromosomal changes are two factors that have been suggested to be involved in psychiatric disorders. Indeed, numerous risk loci have been identified in autism spectrum disorders, schizophrenia, and related psychiatric disorders. Here, we introduce genetic animal models that disturb excitatory-inhibitory balance in the brain and animal models mirroring human chromosomal abnormalities, both of which may be implicated in autism spectrum disorder pathophysiology. In addition, we discuss recent unique translational research using rodent models, such as Cntnap2 knockout mouse, Mecp2 mutant mouse, Pick1 knockout mouse, and neonatal ventral hippocampal lesion rat. By using these models, several types of drugs are administered during the developmental period to see the effect on psychotic symptoms and neural activities in adults. The accumulating evidence from recent animal studies provides an informative intervention strategy as a translational research.

Toward early estimation and treatment of addiction vulnerability: radial arm maze and N-acetyl cysteine before cocaine sensitization or nicotine self-administration in neonatal ventral hippocampal lesion rats.

RationalPrefrontal cortical (PFC)–hippocampal–striatal circuits, interconnected via glutamatergic signaling, are dysfunctional in mental illnesses that involve addiction vulnerability.ObjectivesIn healthy and neurodevelopmentally altered rats, we examined how Radial Arm Maze (RAM) performance estimates addiction vulnerability, and how starting a glutamatergic modulating agent, N-acetyl cysteine (NAC) in adolescence alters adult mental illness and/or addiction phenotypes.MethodsRats with neonatal ventral hippocampal lesions (NVHL) vs. SHAM-operated controls were randomized to NAC vs. saline in adolescence followed by cognitive testing (RAM) in early adulthood and then cocaine behavioral sensitization (experiment 1; n = 80) or nicotine self-administration (experiment 2; n = 12).ResultsIn experiment 1, NVHL rats showed over-consumption of food (Froot-Loops (FL)) baiting the RAM with poor working memory (low-arm entries to repeat (ETR)), producing an elevated FL to ETR ratio (“FLETR”; p < 0.001). FLETR was the best linear estimator (compared to FL or ETR) of magnitude of long-term cocaine sensitization (R 2 = 0.14, p < 0.001). NAC treatment did not alter FL, ETR, FLETR, or cocaine sensitization. In experiment 2, FLETR also significantly and uniquely correlated with subsequent drug seeking during nicotine-induced reinstatement after extinction of nicotine self-administration (R 2 = 0.47, p < 0.01). NAC did not alter RAM performance, but significantly reversed NVHL-induced increases in nicotine seeking during extinction and reinstatement.ConclusionsThese findings demonstrate the utility of animal models of mental illness with addiction vulnerability for developing novel diagnostic measures of PFC–hippocampal–striatal circuit dysfunction that may reflect addiction risk. Such tests may direct pharmacological treatments prior to adulthood and addictive drug exposure, to prevent or treat adult addictions.

Role of hippocampus in polymodal-cue guided tasks in rats

To examine how signals from different sensory modalities are integrated to generate an appropriate goal-oriented behavior, we trained rats in an eight-arm radial maze to visit a cue arm provided with intramaze cues from different sensory modalities, i.e. visual, tactile and auditory, in order to obtain a reward. When the same rats were then examined on test trials in which the cue arm contained one of the stimuli that the animals were trained with (i.e. light, sound or rough sheet), they showed a significant impairment with respect to the performance on the polymodal-cue task. The contribution of the dorsal hippocampus to the acquisition and retention of polymodal-cue guided task was also examined. We found that rats with dorsal hippocampal lesions before training showed a significant deficit in the acquisition of polymodal-cue oriented task that improved with overtraining. The selective lesion of the dorsal hippocampus after training disrupted memory retention, but the animals' performance improved following retraining of the polymodal task. All hippocampal lesioned rats displayed an impaired performance on the unimodal test. These findings suggest that the dorsal hippocampus contributes to the processing of multimodal sensory information for the associative memory formation and consolidation.

Western diet and the weakening of the interoceptive stimulus control of appetitive behavior

In obesogenic environments food-related external cues are thought to overwhelm internal cues that normally regulate energy intake. We investigated how this shift from external to internal stimulus control might occur. Experiment 1 showed that rats could use stimuli arising from 0 and 4h food deprivation to predict sucrose delivery. Experiment 2 then examined (a) the ability of these deprivation cues to compete with external cues and (b) how consuming a Western-style diet (WD) affects that competition. Rats were trained to use both their deprivation cues and external cues as compound discriminative stimuli. Half of the rats were then placed on WD while the others remained on chow, and external cues were removed to assess learning about deprivation state cues. When tested with external cues removed, chow-fed rats continued to discriminate using only deprivation cues, while WD-fed rats did not. The WD-fed group performed similarly to control groups trained with a noncontingent relationship between deprivation cues and sucrose reinforcement. Previous studies provided evidence that discrimination based on interoceptive deprivation cues depends on the hippocampus and that WD intake could interfere with hippocampal functioning. A third experiment assessed the effects of neurotoxic hippocampal lesions on weight gain and on sensitivity to the appetite-suppressing effects of the satiety hormone cholecystokinin (CCK). Relative to controls, hippocampal-lesioned rats gained more weight and showed reduced sensitivity to a 1.0ug but not 2.0 or 4.0ug CCK doses. These findings suggest that WD intake reduces utilization of interoceptive energy state signals to regulate appetitive behavior via a mechanism that involves the hippocampus.

The sigma agonist 1,3-di-o-tolyl-guanidine reduces the morphological and behavioral changes induced by neonatal ventral hippocampus lesion in rats.

Sigma (σ) receptors have generated a great deal of interest due to their possible role in psychosis, neuroprotection, and various other behaviors including addictive processes. Sigma receptors have been located in brain areas involved in motor functions, including the dopaminergic projections from the substantia nigra to the striatum. Evidence suggests that one of their major roles might be to regulate the activity of the glutamatergic system via the N-methyl-D-aspartate receptor. The sigma receptor agonist 1,3-di-o-tolyl-guanidine (DTG) was found to increase dopamine release in the striatum, nucleus accumbens, and prefrontal cortex, in a dose-dependent manner, after central as well as peripheral administration, suggesting a modulatory role of these receptors on the dopaminergic system. The present study examines whether chronic administration of the DTG sigma agonist induces neuromorphological and behavioral changes in neonatal ventral hippocampal lesioned (nVHL) rats as a neurodevelopmental model of schizophrenia. The results show that the DTG administration reduces the hyperlocomotor activity in nVHL rats and reverses the neuronal hypotrophy generated in nVHL rats in the prefrontal cortex, amygdala, and nucleus accumbens. Our results demonstrate that DTG, a sigma-1 receptor agonist, reverses some of the behavioral and neuromorphological effects of nVHL on the rat and supports the possibility that DTG may have beneficial effects in the management of symptoms of schizophrenia.

Hippocampus, delay discounting, and vicarious trial-and-error.

In decision-making, an immediate reward is usually preferred to a delayed reward, even if the latter is larger. We tested whether the hippocampus is necessary for this form of temporal discounting, and for vicarious trial-and-error at the decision point. Rats were trained on a recently developed, adjustable delay-discounting task (Papale et al. (2012) Cogn Affect Behav Neurosci 12:513-526), which featured a choice between a small, nearly immediate reward, and a larger, delayed reward. Rats then received either hippocampus or sham lesions. Animals with hippocampus lesions adjusted the delay for the larger reward to a level similar to that of sham-lesioned animals, suggesting a similar valuation capacity. However, the hippocampus lesion group spent significantly longer investigating the small and large rewards in the first part of the sessions, and were less sensitive to changes in the amount of reward in the large reward maze arm. Both sham- and hippocampus-lesioned rats showed a greater amount of vicarious trial-and-error on trials in which the delay was adjusted. In a nonadjusting version of the delay discounting task, animals with hippocampus lesions showed more variability in their preference for a larger reward that was delayed by 10 s compared with sham-lesioned animals. To verify the lesion behaviorally, rat were subsequently trained on a water maze task, and rats with hippocampus lesions were significantly impaired compared with sham-lesioned animals. The findings on the delay discounting tasks suggest that damage to the hippocampus may impair the detection of reward magnitude.

Nicotine effects in adolescence and adulthood on cognition and α₄β₂-nicotinic receptors in the neonatal ventral hippocampal lesion rat model of schizophrenia.

Nicotine use in schizophrenia has traditionally been explained as "self-medication" of cognitive and/or nicotinic acetylcholinergic receptor (nAChR) abnormalities. We test this hypothesis in a neurodevelopmental rat model of schizophrenia that shows increased addiction behaviors including enhanced nicotine reinforcement and drug-seeking. Nicotine transdermal patch (5 mg/kg/day vs. placebo × 10 days in adolescence or adulthood) effects on subsequent radial-arm maze learning (15 sessions) and frontal-cortical-striatal nAChR densities (α4β2; [3H]-epibatidine binding) were examined in neonatal ventral hippocampal lesion (NVHL) and SHAM-operated rats. NVHL cognitive deficits were not differentially affected by nicotine history compared to SHAMs. Nicotine history produced minimal cognitive effects while increasing food-reward consumption on the maze, compounding with NVHL-induced overconsumption. Acute nicotine (0.5 mg/kg) delivered before the final maze sessions produced modest improvements in maze performance in rats with nicotine patch histories only, but not differentially so in NVHLs. Consistent with in vivo neuroimaging of β2 nAChR binding in schizophrenia smokers vs. non-smokers and healthy controls, adult NVHLs showed 12% reductions in nAChR binding in MPFC (p < 0.05) but not ventral striatum (<5% changes, p > .40), whereas nicotine history elevated nAChRs across both regions (>30%, p < 0.001) without interacting with NVHLs. Adolescent vs. adult nicotine exposure did not alter nAChRs differentially. Although replicating nicotine-induced upregulation of nAChRs in human smokers and demonstrating NVHL validity in terms of schizophrenia-associated nAChR density patterns, these findings do not support hypotheses explaining increased nicotine use in schizophrenia as reflecting illness-specific effects of nicotine to therapeutically alter cognition or nAChR densities.