Deep behavioural phenotyping of the Q175 Huntington disease mouse model: effects of age, sex, and weight.

BACKGROUND: Huntington disease (HD) is a neurodegenerative disorder with complex motor and behavioural manifestations. The Q175 knock-in mouse model of HD has gained recent popularity as a genetically accurate model of the human disease. However, behavioural phenotypes are often subtle and progress slowly in this model. Here, we have implemented machine-learning algorithms to investigate behaviour in the Q175 model and compare differences between sexes and disease stages. We explore distinct behavioural patterns and motor functions in open field, rotarod, water T-maze, and home cage lever-pulling tasks. RESULTS: In the open field, we observed habituation deficits in two versions of the Q175 model (zQ175dn and Q175FDN, on two different background strains), and using B-SOiD, an advanced machine learning approach, we found altered performance of rearing in male manifest zQ175dn mice. Notably, we found that weight had a considerable effect on performance of accelerating rotarod and water T-maze tasks and controlled for this by normalizing for weight. Manifest zQ175dn mice displayed a deficit in accelerating rotarod (after weight normalization), as well as changes to paw kinematics specific to males. Our water T-maze experiments revealed response learning deficits in manifest zQ175dn mice and reversal learning deficits in premanifest male zQ175dn mice; further analysis using PyMouseTracks software allowed us to characterize new behavioural features in this task, including time at decision point and number of accelerations. In a home cage-based lever-pulling assessment, we found significant learning deficits in male manifest zQ175dn mice. A subset of mice also underwent electrophysiology slice experiments, revealing a reduced spontaneous excitatory event frequency in male manifest zQ175dn mice. CONCLUSIONS: Our study uncovered several behavioural changes in Q175 mice that differed by sex, age, and strain. Our results highlight the impact of weight and experimental protocol on behavioural results, and the utility of machine learning tools to examine behaviour in more detailed ways than was previously possible. Specifically, this work provides the field with an updated overview of behavioural impairments in this model of HD, as well as novel techniques for dissecting behaviour in the open field, accelerating rotarod, and T-maze tasks.

Learning the native pond odor as one of the mechanisms of olfactory orientation in juvenile smooth newt Lissotriton vulgaris.

Olfaction is an important mechanism of orientation in amphibians toward the breeding site. It is known that anurans can memorize the odor of the native pond during larval development and prefer this odor prior to the beginning of dispersion. However, such a mechanism in urodeles has not been studied yet. We conducted experiments on recognition of the odor of a native water body in juveniles of the smooth newt Lissotriton vulgaris. One group of larvae were reared in pure water (control), the other group in water with morpholine (10-7 mol/L). A few days after metamorphosis, the newts were tested under paired-choice conditions in a T-maze. A total of 73 newts from the experimental group and 47 newts from the control group were tested. The results of the experiment show that the newts in the experimental group preferred the morpholine solution, whereas the individuals of the control group made the choice randomly. We conclude that newts can learn the odor of the environment in which they developed and use this memory for orientation in later stages of life.

Maze design: size and number of choices impact fish performance in cognitive assays.

Although studies on fish cognition are increasing, consideration of how methodological details influence the ability to detect and measure performance is lagging. Here, in two separate experiments the authors compared latency to leave the start position, latency to make a decision, levels of participation and success rates (whether fish entered the rewarded chamber as first choice) across different physical designs. Experiments compared fish performance across (a) two sizes of T-mazes, large and standard, and a plus-maze, and (b) open choice arenas with either two or four doors. Fish in T-mazes with longer arms took longer to leave the start chamber and were less likely to participate in a trial than fish in T-mazes with shorter arms. The number of options, or complexity, in a maze significantly impacted success but did not necessarily impact behavioural measures, and did not impact the number of fish that reached a chamber. Fish in the plus-maze had similar latencies to leave the start box and time to reach any chamber as fish in the same-sized T-maze but exhibited lower overall success. Similarly, in an open choice arena, increasing the number of options - doors to potential reward chambers - resulted in lower probability of success. There was an influence of reward position in the choice arena, with rewarded chambers closest to the sides of the arena resulting in lower latencies to enter and higher probability of decision success. Together the results allow the authors to offer practical suggestions towards optimal maze design for studies of fish cognition.

Lantana camara leaf extract ameliorates memory deficit and the neuroinflammation associated with scopolamine-induced Alzheimer's-like cognitive impairment in zebrafish and mice.

CONTEXT: Lantana camara Linn. (Verbenaceae) is used for improving memory in certain African societies. OBJECTIVE: This study investigated the effect of prophylactic treatment with hydroethanolic leaf extract of Lantana camara (LCE) on short-term memory deficit and neuroinflammation induced with scopolamine in zebrafish and mice. MATERIALS AND METHODS: Zebrafish (AB strain) and mice (ICR) were given donepezil (0.65 mg/kg, oral) and LCE (10, 30, 100 mg/kg, oral) for 7, and 10 days, respectively, before induction of cognitive impairment with scopolamine immersion (200 µM) and intraperitoneal injection (2 mg/kg), respectively. Spatial short-term memory was assessed in zebrafish using both Y- and T-mazes, whereas Y-maze was used in mice. Mice hippocampal and cortical tissues were analyzed for mRNA expression of proinflammatory genes (IL-1ß, IL-6, TNF-α, COX-2) using qRT-PCR. RESULTS: In the zebrafish Y-maze, LCE (10 and 100 mg/kg) increased time spent in the novel arm by 55.89 ± 5.70%, and 68.21 ± 2.75%, respectively, but not at 30 mg/kg. In the zebrafish T-maze, there was an increase in time spent in the food-containing arm at 30 (44.23 ± 2.13) and 100 mg/kg (52.30 ± 1.94). In the mouse Y-maze, spontaneous alternation increased by 52.89 ± 4.98% at only 10 mg/kg. LCE (10, 30, 100 mg/kg) inhibited proinflammatory gene (IL-1ß, IL-6, TNF-α, COX-2) mRNA expression, with the highest inhibitory effect on IL-6 in both the hippocampus (83.27 ± 2.49%; 100 mg/kg) and the cortex (98.74 ± 0.11%; 10 mg/kg). DISCUSSION AND CONCLUSION: LCE ameliorated scopolamine-induced AD in both zebrafish and mice.

Progesterone rapidly alters the use of place and response memory during spatial navigation in female rats.

17ß-Estradiol (E2) and progesterone (P) influence place and response memory in female rats in spatial navigation tasks. Use of these memory systems is associated with the hippocampus and the dorsal striatum, respectively. Injections of E2 result in a well-established bias to use place memory, while much less is understood about the role of P. A total of 120 ovariectomized female rats were tested within a dual-solution T-maze task and treated with either low E2 (n = 24), high E2 (10 µg/kg; n = 24), or high E2 in combination with P (500 µg/kg) at three time points before testing: 15 min (n = 24), 1 h (n = 24), and 4 h (n = 24). Given alone, high E2 biases rats to the use of place memory, but this effect is reversed when P is given 1 h or 4 h before testing. This indicates that P may be playing an inhibitory role in the hippocampus during spatial tasks, which is consistent with past findings. Our findings show that P acts rapidly (within an hour) to affect performance during spatial tasks.

Operant conditioning in antlion larvae and its impairment following exposure to elevated temperatures.

Although ambush predators were previously considered limited in their cognitive abilities compared to their widely foraging relatives, there is accumulating evidence it does not hold true. Pit-building antlions are already known to associate vibrations in the sand with the arrival of prey. We used a T-maze and successfully trained antlions to turn right or left against their initial turning bias, leading to a suitable substrate for digging traps. We present here the first evidence for operant conditioning and T-maze solving in antlions. Furthermore, we show that exposure of second instar larvae to an elevated temperature led to impaired retention of what was learned in a T-maze when tested after moulting into the third instar, compared to larvae raised under a more benign temperature. We suggest that climate change, involving an increase in mean temperatures as well as rare events (e.g., heatwaves) might negatively affect the retention of operant conditioning in antlions, alongside known, more frequently studied effects, such as changes in body size and distribution.

Reproduction-related interactions and loads induce continuous turn alternation leading to linearity in a terrestrial isopod.

Turn alternation (TA) is the tendency to turn in the opposite direction of an immediately preceding turn when moving forward, resulting in an overall linear trajectory. TA has been observed in many animals, and terrestrial isopods are considered model organisms for studying TA. Optimizing their fleeing speed and trajectory helps isopods efficiently escape from predatory threats. However, since reproduction induces morphological and physiological changes, individuals might adjust their trajectories depending on their altered mobility. In this study, we investigated the effect of reproduction-related factors on the frequency of TA, which enables linearity, in the common rough woodlouse Porcellio scaber. The results showed that breeding females enhanced their linearity more than nonbreeding females and males. Furthermore, females without access to a potential mate enhanced their linearity more than females and males with access to a potential mate and maintained a high linearity for approximately 40 days. In terrestrial isopods, continuous TA for linearity may be used to avoid reproductive failure because of lack of encounters with the potential mate or to compensate for low running ability due to physical or physiological loads. Conversely, individuals that do not need to worry about reproductive failures or individuals with small loads could perform the random turn that does not require learning or memory. This is the first study to show that the events involved in reproduction affect the linearity shown by continuous TA in terrestrial isopods.

Repeatability of lateralisation in mosquitofish Gambusia holbrooki despite evidence for turn alternation in detour tests.

Akin to handedness in humans, some animals show a preference for moving to the left or right. This is often attributed to lateralised cognitive functions and eye dominance, which, in turn, influences their behaviour. In fishes, behavioural lateralisation has been tested using detour mazes for over 20 years. Studies report that certain individuals are more likely to approach predators or potential mates from one direction. These findings imply that the lateralisation behaviour of individuals is repeatable, but this is rarely confirmed through multiple testing of each individual over time. Here we quantify the repeatability of turning behaviour by female mosquitofish (Gambusia holbrooki) in a double sided T-maze. Each female was tested three times in each of six treatments: when approaching other females, males, or an empty space; and when able to swim freely or when forced to choose by being herded from behind with a net. Although there was no turning bias based on the mean population response, we detected significant repeatability of lateralisation in five of the six treatments (R = 0.251-0.625). This is noteworthy as we also found that individuals tended to alternate between left and right turns, meaning that they tend to move back and forth along one wall of the double-sided T-maze. Furthermore, we found evidence for this wall following when re-analysing data from a previous study. We discuss potential explanations for this phenomenon, and its implications for study design.

Repeated crack cocaine administration alters panic-related responses and delta FosB immunoreactivity in panic-modulating brain regions.

Crack cocaine is the crystal form of cocaine, produced by adding sodium bicarbonate to cocaine base paste. Brazil is the largest consumer of crack cocaine in the world. Users of crack cocaine show important physiological and behavioral alterations, including neuropsychiatric symptoms, such as anxiety-related symptoms. Nevertheless, few pre-clinical studies have been previously performed to understand the neurobiological effects of crack cocaine. The purpose of the present study was to investigate effects of the subchronic treatment (5 days, IP) of rats with crack cocaine in an animal model of anxiety/panic, the elevated T-maze (ETM). The ETM model allows the measurement of two behavioral defensive responses, avoidance and escape, in clinical terms, respectively, associated to generalized anxiety and panic disorder, the two main psychiatric conditions that accompany substance use disorders. Immediately after the ETM model, animals were tested in an open field for locomotor activity assessment. Analysis of delta FosB protein immunoreactivity was used to map areas activated by crack cocaine exposure. Results showed that crack treatment selectively altered escape displayed by rats in the ETM test, inducing either a panicolytic (18 mg/kg IP) or a panicogenic-like effect (25 and 36 mg/kg IP). These effects were followed by the altered functioning of panic-modulating brain regions, i.e., the periaqueductal gray and the dorsal region and lateral wings of the dorsal raphe nucleus. Treatment with 36 mg/kg of crack cocaine also increased locomotor activity. These are the first observations performed with crack cocaine in a rodent model of anxiety/panic and contribute to a better understanding of the behavioral and neurobiological effects of crack cocaine.

Visuo-motor biases in buff-tailed bumblebees (Bombus terrestris).

Bees provide a good model to investigate the evolution of lateralization. So far, most studies focused on olfactory learning and memories in tethered bees. This study investigated possible behavioural biases in free-flying buff-tailed bumblebees (Bombus terrestris) by analysing their turning decisions in a T-maze. Bees of various size were trained to associate a syrup reward with a blue target placed at the centre of the T-maze. The bees were then tested over 16 trials by presenting them with blue targets at the end of the maze's arms. The maze was rotated 180° after the first 8 trials to control for environmental factors. The number of turnings to the left and right arms were analysed. The bees sampled exhibited a population-level rightward turning bias. As bumblebees vary significantly in size with large bees being better learners than smaller ones, we measured the thorax width to identify a possible relationship between size and bias. No significant correlation was identified. This study shows that bees present lateralization in a visuo-motor task that mimics their foraging behaviour, indicating a possible specialization of the right side of the nervous system in routine tasks.

The effect of copper on behaviour, memory, and associative learning ability of zebrafish (Danio rerio).

Copper is an essential element in many biological processes, but may exert toxic effects at levels surplus to metabolic requirements. Herein we assess the effect of copper on zebrafish behaviour using two assays, namely the novel tank diving test and a T-maze test with food reward. Novel tank diving tests were conducted on days 0, 4, and 10 of a 10 day Cu exposure (at concentrations of 0.77 µM (25% of the 240 h LC50) and 1.52 µM (50% of the 240 h LC50) to assess the alterations of behavioural responses in repeating novel tank diving assays and the effect of Cu on these patterns. Results demonstrate habituation to novelty, which is an indicator of spatial memory. Copper exposure had no effect on the latency of entry into the upper zones of the tank, nor on the total time spent therein, but did cause a greater number of freezing bouts in comparison to the control group. Additionally, Cu exposure had no effect on the habituation responses of zebrafish. Using the T-maze assay, we tested the effect of prior exposure to Cu for 10 days on subsequent behavioural trainings. The T-maze protocol was based on associative learning, where a visual stimulus (colour) was linked with a natural stimulus (food). Results of the control group showed that zebrafish are able to perform associative learning tasks. Moreover, Cu was found to negatively affect the associative learning capabilities. Specifically, while zebrafish in the control group achieved a significant number of correct choices (leading to food reward) throughout the T-maze training, such a trend was not observed for Cu exposed fish. Thus at the exposure concentrations and exposure times considered herein, Cu has no determinative impact on instinctual behavioural responses of zebrafish in repeated novel tank diving assays but does limit the associative learning capabilities.

Development of a Modified Three-Day T-maze Protocol for Evaluating Learning and Memory Capacity of Adult Zebrafish.

A T-maze test is an experimental approach that is used in congenital research. However, the food reward-based protocol for the T-maze test in fish has low efficiency and a long training period. The aim of this study is to facilitate the T-maze conditions by using a combination of the principles of passive avoidance and a spatial memory test. In our modified T-maze settings, electric shock punishment (1-2 V, 0.3-0.5 mA) is given at the left arm, with a green cue at the right arm. Also, the depth of both arms of the T-maze was increased. The parameters measured in our T-maze design were latency, freezing time, and time spent in different areas of the T-maze. We validated the utility of our modified T-maze protocol by showing the consistent finding of memory impairment in ZnCl2-treated fish, which has been previously detected with the passive avoidance test. In addition, we also tested the spatial memory performance of leptin a (lepa) mutants which displayed an obesity phenotype. The results showed that although the learning and memory performance for lepa KO fish were similar to control fish, they displayed a higher freezing behavior during the training phase. In conclusion, we have established a modified T-maze protocol that can be used to evaluate the anxiety, learning, and memory capacity of adult zebrafish within three days, for the first time.

Pterostilbene Improves Cognitive Performance in Aged Rats: An in Vivo Study.

BACKGROUND/AIMS: Pterostilbene (Pt; trans-3,5-dimethoxy-4'-hydroxystilbene) is a natural phenol found in blueberries and grapevines. It shows remarkable biomedical activities similar to those of resveratrol. Its high bioavailability is a major advantage for possible biomedical applications. The goal of the study was to evaluate the effects of chronic pterostilbene administration on cognitive performance in aged rats with mild cognitive impairment. METHODS: 18-month-old animals were subjected to behavioral tests to establish the "baseline", then divided into treatment and control groups. The former were chronically fed Pt (22.5 mg/kg-day) for 20 consecutive days. At the end of this period all animals were tested again and sacrificed. The dentate gyrus, the hippocampus and the prefrontal and perirhinal cortices were then collected, and RT-qPCR and/or Western blot analyses were performed on a few transcripts/proteins involved in synaptic remodeling. Mitochondrial content was also assessed. RESULTS: Pt administration improved performance in behavioral tests and positively affected memory consolidation. We found increased levels of REST, PSD-95 and mitochondrial porin1 in the dentate gyrus and a positive correlation between T-maze test score and levels of cAMP responsive element binding protein (CREB) phosphorylation. CONCLUSION: These results underscore the therapeutic potential of Pt supplementation for age-related cognitive decline.

Chronic administration of gonadotropin releasing-hormone improves learning in old gonadectomized rats.

The aim of this study was to determine whether chronic administration of GnRH improves performance of learning tasks and expression of spinophilin in the hippocampus of gonadectomized old rats. Eighteen-month-old male Wistar rats were used and divided into three groups: control (intact rats); gonadectomized; and gonadectomized + GnRH. The latter group was injected intramuscularly with GnRH (100 nM) twice a day for five weeks. The learning tasks we used were the novel object recognition task (NOR), elevated T-maze (ETM) and active avoidance test (AAT). Results showed that in NOR and ETM learning tasks, gonadectomized rats treated with GnRH had a significantly better performance than gonadectomized rats without treatment. GnRH-treated gonadectomized rats displayed performance comparable to that of intact rats. Furthermore, the expression of spinophilin in the hippocampus of gonadectomized rats treated with GnRH increased with respect to untreated gonadectomized rats. In conclusion, the chronic administration of GnRH improves learning in old gonadectomized rats. It is possible that the mechanism could involve a greater number of dendritic contacts associated with a higher expression of spinophilin.

Mir363-3p attenuates post-stroke depressive-like behaviors in middle-aged female rats.

Women are more likely to develop Post Stroke Depression (PSD) than men and generally do not respond well to anti-depressants with age. This study investigated the effect of microRNA mir363-3p treatment on PSD using a physiologically-relevant animal model. Our previous work showed that mir363-3p treatment, delivered post-stroke, effectively reduces infarct volume in the acute phase of stroke in middle-aged females but not males. Middle-aged female Sprague Dawley rats were tested for baseline sensory motor function and depressive-like behaviors, and then subjected to ischemic stroke via middle cerebral artery occlusion (MCAo) or sham surgery. Animals received either control oligos (MCAo+scrambled, Sham+scrambled) or mir363-3p (MCAo+mir363-3p, Sham+mir363-3p) treatment 4 h later. Sensory motor function and depressive-like behaviors were reassessed up to 100 d after stroke, and circulating levels of IL-6, TNF-alpha and Brain-Derived Neurotrophic Factor (BDNF) were quantified at regular intervals. Prior to termination, Fluorogold was injected into the striatum to assess meso-striatal projections. MCAo+scrambled animals had impaired sensorimotor performance in the acute phase (5 days) of stroke and developed anhedonia, decreased sociability and increased helplessness in the chronic phase. MCAo+mir363-3p animals showed significantly less sensory motor impairment and fewer depressive-like behaviors. IL-6 and TNF-alpha were elevated transiently at 4 weeks after MCAo in both groups. BDNF levels decreased progressively after stroke in the MCAo+scrambled group, and this was attenuated in the mir363-3p group. The number of retrogradely-labeled SNc and VTA cells was reduced in the ischemic hemisphere of the MCAo+scrambled group. In contrast, there was no interhemispheric difference in the number of retrogradely-labeled SNc and VTA cells of MCAo+mir363-3p treated animals. Our results support a therapeutic role for mir363-3p for long-term stroke disability.

High-beta/low-gamma frequency activity reflects top-down predictive coding during a spatial working memory test.

Numerous mental health disorders are characterized by cognitive impairments that result in poor vocational and social outcomes. Among the cognitive domains commonly affected, working memory deficits have been noted in patients with attention-deficit/hyperactivity disorder (Martinussen et al. in J Am Acad Child Adolesc Psychiatry 44:377-384, 2005), post-traumatic stress disorder (Honzel et al. in Cogn Affect Behav Neurosci 14:792-804, 2014), and consistently with schizophrenia patients (Callicott et al. in Cereb Cortex 10:1078-1092, 2000; Lewis et al. in Front Hum Neurosci 10:85, 2005; Amann et al. in Brain Res Bull 83:147-161, 2010; Limongi et al. in Schizophr Res 197:386-391, 2018). Oscillations in neural activity from electroencephalogram (EEG) recordings are decomposed by frequency, and band-specific decreases in gamma power (> 30 Hz) have been correlated with working memory ability. This study examined within-subject changes in power of frequency-specific bands during sample versus choice trials during a spatial working memory paradigm (T-maze). EEG was recorded using a relatively novel wireless EEG telemetry system fully implanted within the mouse, enabling uninhibited movement during behavioral tasks. No significant differences were found between sample and correct choice phases in the alpha, theta or gamma frequency ranges. Evoked power was significantly higher during the choice phase than the sample phase in the high-beta/low-gamma frequency range. This frequency range has been implicated in the propagation of cortical predictions to lower levels of stimuli encoding in a top-down hierarchical manner. Results suggest there is an increase in brain activity during correct trials when the mouse enters the opposite arm during the choice phase compared to the sample phase, likely due to prediction error resulting from a discrepancy between present and prior experience. Future studies should identify specific cortical networks involved and investigate neural activity at the neuronal level.

Sex differences in discrimination reversal learning in the guppy.

In several mammalian and avian species, females show a higher performance than males in tasks requiring cognitive flexibility such as the discrimination reversal learning. A recent study showed that female guppies are twice as efficient as males in a reversal learning task involving yellow-red discrimination, suggesting a higher cognitive flexibility in female guppies. However, the possibility exists that the superior performance exhibited by females does not reflect a general sex difference in cognitive abilities, but instead, is confined to colour discrimination tasks. To address this issue, we compared male and female guppies in two different discrimination reversal learning tasks and we performed a meta-analysis of these experiments and the previous one involving colour discrimination. In the first experiment of this study, guppies were tested in a task requiring them to learn to select the correct arm of a T-maze in order to rejoin a group of conspecifics. In experiment 2, guppies were observed in a numerical task requiring them to discriminate between 5 and 10 dots in order to obtain a food reward. Although females outperformed males in one condition of the T-maze, we did not find any clear evidence of females' greater reversal learning performance in either experiment. However, the meta-analysis of the three experiments supported the hypothesis of females' greater reversal learning ability. Our data do not completely exclude the idea that female guppies have a generally higher cognitive flexibility than males; however, they suggest that the size of this sex difference might depend on the task.

Humanized Foxp2 accelerates learning by enhancing transitions from declarative to procedural performance.

The acquisition of language and speech is uniquely human, but how genetic changes might have adapted the nervous system to this capacity is not well understood. Two human-specific amino acid substitutions in the transcription factor forkhead box P2 (FOXP2) are outstanding mechanistic candidates, as they could have been positively selected during human evolution and as FOXP2 is the sole gene to date firmly linked to speech and language development. When these two substitutions are introduced into the endogenous Foxp2 gene of mice (Foxp2(hum)), cortico-basal ganglia circuits are specifically affected. Here we demonstrate marked effects of this humanization of Foxp2 on learning and striatal neuroplasticity. Foxp2(hum/hum) mice learn stimulus-response associations faster than their WT littermates in situations in which declarative (i.e., place-based) and procedural (i.e., response-based) forms of learning could compete during transitions toward proceduralization of action sequences. Striatal districts known to be differently related to these two modes of learning are affected differently in the Foxp2(hum/hum) mice, as judged by measures of dopamine levels, gene expression patterns, and synaptic plasticity, including an NMDA receptor-dependent form of long-term depression. These findings raise the possibility that the humanized Foxp2 phenotype reflects a different tuning of corticostriatal systems involved in declarative and procedural learning, a capacity potentially contributing to adapting the human brain for speech and language acquisition.

Medial septum-diagonal band of Broca (MSDB) GABAergic regulation of hippocampal acetylcholine efflux is dependent on cognitive demands.

The septohippocampal pathway contains cholinergic, GABAergic, and glutamatergic projections and has an established role in learning, memory, and hippocampal theta rhythm. Both GABAergic and cholinergic neurons in the medial septum-diagonal band of Broca (MSDB) have been associated with spatial memory, but the relationship between the two neuronal populations is not fully understood. The present study investigated the effect of selective GABAergic MSDB lesions on hippocampal acetylcholine (ACh) efflux and spatial memory during tasks that varied in memory demand. Male Sprague Dawley rats were given GABAergic lesions of the MSDB using GAT1-saporin (GAT1-SAP) and examined on spontaneous exploration (Experiment 1) and non-matching to position without (NMTP; Experiment 2) and with a delay (DNMTP; Experiment 3), while concurrently using in vivo microdialysis to measure hippocampal ACh efflux. Intraseptal GAT1-SAP treatment did not alter baseline or behaviorally stimulated hippocampal ACh efflux or maze exploration (Experiment 1). Moreover, GAT1-SAP did not alter evoked hippocampal ACh efflux related to NMTP nor did it impair working memory in NMTP (Experiment 2). In contrast, both ACh efflux and performance in DNMTP were impaired by intraseptal GAT1-SAP. Thus, GABAergic MSDB neurons are important for spatial working memory and modulate hippocampal ACh efflux under conditions of high memory load. The relationship between the septohippocampal cholinergic and GABAergic systems and working memory will be discussed.

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.