Reduction of hippocampal new-born neurons survival by working memory training with delayed non-matching to sample task in rats

Adult neurogenesis in the hippocampus is important for learning and memory, and the survival of new-born neurons is modulated by stress, exercise, learning, etc. It has been reported that survival of new-born neurons is also affected by working memory training (WMT). However, the behavioral task for WMT used in previous studies was the task with Morris water maze, in which effects of severe stress and exercise by forced swimming should be considered. Therefore, it is unclear whether WMT effect is due to working memory use alone or not. In the present study, we subjected rats to fourteen days of WMT using a delayed non-matching to sample task with reward in an operant chamber in which no severe stress and exercise were required. The results showed that the number of BrdU positive cells after WMT was decreased without any increase of the movement activity during the WMT and the plasma corticosterone level after WMT. In conclusion, this study suggests for the first time that WMT reduces the survival of hippocampal new-born neurons independently of stress and exercise.

In utero Δ9-tetrahydrocannabinol exposure confers vulnerability towards cognitive impairments and alcohol drinking in the adolescent offspring: Is there a role for neuropeptide Y?

Background: Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life. Aims: This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulnerability in adolescent offspring. NPY and excitatory postsynaptic density (PSD) machinery were measured as markers of neurobiological vulnerability. Methods: Following in utero THC exposure (2 mg/kg delivered subcutaneously), preadolescent male rat offspring were assessed for: behavioural reactivity in the open field test, neutral declarative memory and aversive limbic memory in the Novel Object and Emotional Object Recognition tests, immunofluorescence for NPY neurons and the PSD proteins Homer-1, 1b/c and 2 in the prefrontal cortex, amygdala and nucleus accumbens at adolescence (cohort 1); and instrumental learning, alcohol taking, relapse and conflict behaviour in the operant chamber throughout adolescence until early adulthood (cohort 2). Results: In utero THC-exposed adolescent rats showed: (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber. Conclusion: Gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. The abnormalities in NPY signalling and PSD make-up may represent the common neurobiological background, suggesting new targets for future research.

An objective and automated method for evaluating abdominal hyperalgesia in a rat model for endometriosis

Chronic pain and subfertility are the main symptoms of concern in women with endometriosis. In order to find new therapeutic options to suppress the pain, translational animal models are indispensable. We have developed a new automated, experimental setup, with full consideration for animal wellbeing, to determine whether operant behaviour can reveal abdominal hyperalgesia in rats with surgically-induced endometriosis, in order to assess whether abdominal hyperalgesia affect behavioural parameters. Endometriosis was induced by transplantation of uterine fragments in the abdominal cavity. Control groups consisted of sham-operated rats and non-operated rats. We have developed an operant chamber (Skinnerbox) which includes a barrier. The rat can climb the barrier in order to reach the food pellet, increasing in this way the pressure to the abdomen. We show that endometriosis rats collect significantly less sugar pellets when compared with the control rats after the introduction of the barrier. In the Skinnerbox experiment, we showed that in a positive operant setting, the introduction of a barrier results in a contrast of operant behaviour of endometriosis rats and control groups, perchance as a result of abdominal discomfort/hyperalgesia due to surgically-induced endometriosis. This is a promising start for the further development of a refined animal model to monitor abdominal discomfort/hyperalgesia in rats with surgically-induced endometriosis.

Differential Impairments in Incentive Learning Caused by First‐ and Second‐ Generation Antipsychotic Drugs

Schizophrenia is a neuropsychiatric disorder characterized by increased function of dopamine in the brain. Dopamine release is a natural response to reward. It promotes incentive learning (IL), a process by which neutral stimuli acquire the ability to elicit approach and other responses. A recent model characterizes dopamine‐mediated IL as a progressive process with early and late stages accompanied by a shift in neural control from the nucleus accumbens (NAc) to the dorsolateral striatum (DLS). A parallel can be drawn to differences in regionally specific neural responses generated by first‐ and second‐generation antipsychotic drugs (APDs) used to treat schizophrenia. APDs are dopamine receptor antagonists, but first‐generation APDs affect the NAc and DLS while second‐generation APDs affect primarily the NAc. We compared the effects of APDs on IL. Rats (N = 48) were trained to press a lever forfood pellets in an operant chamber. Intraperitoneal injections (1 hr before testing) of the first‐generation APD haloperidol (0,0.05,0.10,0.20 mg/kg) or of the second‐generation APD risperidone (0,0.20,0.40,0.80 mg/kg) induced dose‐dependent suppression of lever pressing on days 1‐4, with the highest dose groups failing to demonstrate any evidence of previous learning on day 5 when tested drug‐free. On days 16‐20 haloperidol induced a day‐to‐day suppression not seen with risperidone. The results suggest that the effects of first‐ and second‐generation APDs on learning processes putatively mediated by the NAc and DLS can be differentiated experimentally. The findings imply that APDs may differentially affect IL inpatients with schizophrenia.

4. Differential Impairments in Incentive Learning Caused by First‐ and Second‐ Generation Antipsychotic Drugs

Schizophrenia is a neuropsychiatric disorder characterized by increased function of dopamine in the brain. Dopamine release is a natural response to reward. It promotes incentive learning (IL), a process by which neutral stimuli acquire the ability to elicit approach and other responses. A recent model characterizes dopamine‐mediated IL as a progressive process with early and late stages accompanied by a shift in neural control from the nucleus accumbens (NAc) to the dorsolateral striatum (DLS). A parallel can be drawn to differences in regionally specific neural responses generated by first‐ and second‐generation antipsychotic drugs (APDs) used to treat schizophrenia. APDs are dopamine receptor antagonists, but first‐generation APDs affect the NAc and DLS while second‐generation APDs affect primarily the NAc. We compared the effects of APDs on IL. Rats (N = 48) were trained to press a lever for food pellets in an operant chamber. Intraperitoneal injections (1 hr before testing) of the first‐generation APD haloperidol (0,0.05,0.10,0.20 mg/kg) or of the second‐generation APD risperidone (0,0.20,0.40,0.80 mg/kg) induced dose‐dependent suppression of lever pressing on days 1‐4, with the highest dose groups failing to demonstrate any evidence of previous learning on day 5 when tested drug‐free. On days 16‐20, haloperidol induced a day‐to‐day suppression not seen with risperidone. The results suggest that the effects of first‐ and second‐generation APDs on learning processes putatively mediated by the NAc and DLS can be differentiated experimentally. The findings imply that APDs may differentially affect IL inpatients with schizophrenia.

Exposure pattern influences the degree of drug-seeking behaviour after withdrawal

ObjectivesThe occurrence of a relapse during abstinence is an important issue that must be addressed during treatment for drug addiction. We investigated the influence of drug exposure pattern on morphine-seeking behaviour following withdrawal. We also studied the role of the hippocampus in this process to confirm its involvement in drug relapse.MethodsMale Sprague–Dawley rats that were trained to self-administer morphine (1.0 mg/kg) using 2, 4, 6, 8, or 10 h daily sessions underwent withdrawal in their home cages and were re-exposed to the operant chamber to evaluate morphine-seeking behaviour. During the relapse session, rats were intravenously injected with morphine (0.25 mg/kg) or saline before re-exposure to the chamber. In the second experiment, rats were administered a microinjection of saline or cobalt chloride (CoCl2, 1 mM), a synaptic blocker, into the CA1 of the hippocampus prior to the relapse test.ResultsIn the first experiment, more morphine-seeking behaviour was observed in the 2 h group (animals trained to self-administer morphine during a 2 h daily session spread over 21 days) during the relapse session, despite all groups being exposed to similar amounts of morphine during the training period before withdrawal. In the second experiment, pretreatment with CoCl2 markedly reduced morphine-seeking behaviour in the 2 h group.ConclusionsThe present findings suggest that the exposure pattern influences the degree of relapse and that control of memorisation is important for prevention of relapse.