Novelty-induced Arousal Research Articles

Modulation of 5-HT7 receptor: effect on object recognition performances in mice

Recent data suggest that 5-HT7 receptors (5-HT7R) are involved in memory processes and, particularly, those related to novelty-induced arousal, even though this remains so far speculative and controversial. In order to assess the role of 5-HT7R in episodic-like memory, mice were administered 5-carboxamidotryptamine (5-CT, a 5-HT1A/1B/1D/7R agonist) and/or SB-269970 (a selective 5-HT7R antagonist) immediately after the acquisition session of the novel object recognition test. The object recognition test was performed in order to assess the effects of modulation of 5-HT7R during consolidation phase on episodic-like memory performances in mice. A protocol including 3 days of familiarisation to the apparatus has been realised in order to decrease the effect of novelty-induced arousal. With a 2-h delay, SB-269970 (3 and 10 mg/kg, administered subcutaneously) impaired the discrimination of the novel object. With a 4-h delay, while control mice were not able to discriminate the novel object, mice treated with 5-CT (1 mg/kg) showed a significant discrimination. This promnesic effect with a long delay is effectively mediated by 5-HT7R activation since it was blocked by SB-269970 (10 mg/kg), but not by WAY-100135 (10 mg/kg) or by GR-127935 (10 mg/kg). These data suggest that 5-HT7R tonically modulates cognitive processes involved in consolidation performances in object recognition. Therefore, 5-HT7R could be a promising target to treat memory dysfunctions (especially episodically related deficits) related to normal or pathological ageing.

TIP39 modulates effects of novelty-induced arousal on memory

Tuberoinfundibular peptide of 39 residues (TIP39) is a neuropeptide localized to neural circuits subserving emotional processing. Recent work showed that mice with null mutation for the gene coding TIP39 (TIP39-KO mice) display increased susceptibility to environmental provocation. Based on this stressor-dependent phenotype, the neuroanatomical distribution of TIP39, and knowledge that novelty-induced arousal modulates memory functions via noradrenergic activation, we hypothesized that exposure to a novel environment differently affects memory performance of mice with or without TIP39 signaling, potentially by differences in sensitivity of the noradrenergic system. We tested TIP39-KO mice and mice with null mutation of its receptor, the parathyroid hormone 2 receptor (PTH2-R), in tasks of short-term declarative and social memory (object recognition and social recognition tests, respectively), and of working memory (Y-maze test) under conditions of novelty-induced arousal or acclimation to the test conditions. Mice lacking TIP39 signaling showed memory impairment selectively under conditions of novelty-induced arousal. Acute administration of a PTH2-R antagonist in wild-type mice had a similar effect. The restoration of memory functions in TIP39-KO mice after injection of a β-adrenoreceptor-blocker, propranolol, suggested involvement of the noradrenergic system. Collectively, these results suggest that the TIP39/PTH2-R system modulates the effects of novelty exposure on memory performance, potentially by acting on noradrenergic signaling.

Novelty-induced arousal enhances memory for cued classical fear conditioning: Interactions between peripheral adrenergic and brainstem glutamatergic systems

Exposure to novel contexts produce heightened states of arousal and biochemical changes in the brain to consolidate memory. However, processes permitting simple exposure to unfamiliar contexts to elevate sympathetic output and to improve memory are poorly understood. This shortcoming was addressed by examining how novelty-induced changes in peripheral and/or central arousal modulates memory for Pavlovian fear conditioning. Male rats were either exposed to the conditioning chamber for 5-min or given no exposure 24 h before conditioning with five tone-shock (0.35 mA) pairings. Retention was assessed 48 h later in a different context. Non-pre-exposed animals exhibited significantly greater freezing during conditioned stimulus (CS) presentations than did pre-exposed animals (P < 0.05). The improvement in retention produced by novelty was attenuated by pretraining a blockade of peripheral beta-adrenergic receptors with sotalol (6 mg/kg, i.p.). Study 2 revealed that novelty-induced increases in peripheral autonomic output are conveyed to the brain by visceral afferents that synapse upon brainstem neurons in the nucleus tractus solitarius (NTS). Blocking AMPA receptor activity in the NTS with CNQX (1.0 microg) significantly reduced freezing to the CS in non-pre-exposed animals (P < 0.01). Study 3 showed that elevating epinephrine levels in habituated animals influences learning through mechanisms similar to those produced by novelty-induced arousal. Pre-exposed animals given epinephrine (0.1 mg/kg) froze significantly more than saline controls (P < 0.01), and this effect was attenuated by intra-NTS infusion of CNQX. The findings demonstrate that novelty-induced arousal or increasing sympathetic activity with epinephrine in pre-exposed animals enhances memory through adrenergic mechanisms initiated in the periphery and transmitted centrally via the vagus/NTS complex.

The histamine H1‐receptor mediates the motivational effects of novelty

Novelty-induced arousal has motivational effects and can reinforce behavior. The mechanisms by which novelty acts as a reinforcer are unknown. Novelty-induced arousal can be either rewarding or aversive dependent on its intensity and the preceding state of arousal. The brain's histamine system has been implicated in both arousal and reinforcement. Histamine and histamine-1-receptor (H1R) agonists induced arousal and wakefulness in humans and rodents, e.g. by stimulating cortical acetylcholine (ACh) release. The H1R has also been implicated in processes of brain reward via interactions with the nigrostriatal- and mesolimbic dopamine (DA) systems. We asked whether the motivational effects of novelty-induced arousal are compromised in H1R knockout (KO) mice. The H1R-KO mice failed to develop a conditioned place-preference induced by novel objects. Even though they still explore novel objects, their reinforcing value is diminished. Furthermore, they showed impaired novelty-induced alternation in the Y-maze. Rearing activity and emotional behavior in a novel environment was also altered in H1R-KO mice, whereas object-place recognition was unaffected. The H1R-KO mice had higher ACh concentrations in the frontal cortex and amygdala (AMY). In the latter, the H1R-KO mice had also increased levels of DA, but a lower dihydrophenylacetic acid/DA ratio. Furthermore, the H1R-KO mice had also increased tyrosine hydroxylase immunoreactivity in the basolateral anterior, basolateral ventral and cortical AMY nuclei. We conclude that the motivational effects of novelty are diminished in H1R-KO mice, possibly due to reduced novelty-induced arousal and/or a dysfunctional brain reward system.

The 5-HT7 receptor: Role in novel object discrimination and relation to novelty-seeking behavior

Despite showing high affinity for neuroleptics and hallucinogens, the function of the 5-HT7 receptor in cognition remains largely speculative. This study tests the hypothesis that 5-HT7 participates in gauging salience of novel visual stimuli as a function of the animal’s initial tendency for novelty-seeking. Novelty-seeking behavior in the rat is thought to model some aspects of sensation-seeking in humans, a personality trait closely associated to drug abuse. We analyzed the effects of the 5-HT7 receptor antagonist SB269.970 (3 mg kg −1 or 15 mg kg −1 i.p.) on object-recognition tasks using rats that differed in exploration of novel environments, namely high (HR) and low (LR) responders. The task involved a first encounter with an object (“old”), which after a delay of 3 h had to be discriminated from a different object (“new”). The antagonist was injected into HR and LR rats immediately after the first encounter with the objects and its effects on recall of objects were evaluated. In the absence of drug, LR but not HR rats were able to discriminate the familiarity of previously encountered objects. A low dose (3 mg kg −1) of SB269.970 was ineffective in altering object discrimination. A higher dose (15 mg kg −1) inhibited novel-object exploration in LR animals thus curtailing differences in object recognition, a finding that was replicated. In order to validate our studies, the effects of the cholinergic muscarinic antagonist scopolamine (0.2 mg kg −1, i.p.) on object recognition were also evaluated in one of the cohorts 2 weeks after the first NOD experiment. In the Choice phase, all vehicle-treated rats succeeded in recognizing the new object. Scopolamine inhibited object discrimination in HR rats more efficiently than it did in LR rats. Taken together, these results suggest that 5-HT7 may mediate attentional and memory processes relevant to novelty-induced arousal.

Cholinergic cells in the nucleus basalis of mice express the N‐methyl‐d‐aspartate‐receptor subunit NR2C and its replacement by the NR2B subunit enhances frontal and amygdaloid acetylcholine levels

It is known that glutamatergic and cholinergic systems interact functionally at the level of the cholinergic basal forebrain. The N-methyl-d-aspartate receptor (NMDA-R) is a multiprotein complex composed of NR1, NR2 and/or NR3 subunits. The subunit composition of NMDA-R of cholinergic cells in the nucleus basalis has not yet been investigated. Here, by means of choline acetyl transferase and NR2B or NR2C double staining, we demonstrate that mice express both the NR2C and NR2B subunits in nucleus basalis cholinergic cells. We generated NR2C-2B mutant mice in which an insertion of NR2B cDNA into the gene locus of the NR2C gene replaced NR2C by NR2B expression throughout the brain. This NR2C-2B mutant was used to examine whether a subunit exchange in cholinergic neurons would affect acetylcholine (ACh) content in several brain structures. We found increased ACh levels in the frontal cortex and amygdala in the brains of NR2C-2B mutant mice. Brain ACh has been implicated in neuroplasticity, novelty-induced arousal and encoding of novel stimuli. We therefore assessed behavioral habituation to novel environments and objects as well as object recognition in NR2C-2B subunit exchange mice. The behavioral analysis did not indicate any gross behavioral alteration in the mutant mice compared with the wildtype mice. Our results show that the NR2C by NR2B subunit exchange in mice affects ACh content in two target areas of the nucleus basalis.

Habituation to the test cage influences amphetamine-induced locomotion and Fos expression and increases FosB/ΔFosB-like immunoreactivity in mice

Pre-exposure to the testing cage (habituation or familiarization) is a common procedure aimed at reducing the interference of novelty-induced arousal and drug-independent individual differences on neural and behavioral measures. However, recent results suggest that this procedure might exert a major influence on the effects of addictive drugs. The present experiments tested the effects of repeated exposure to a test cage (1 h daily for four consecutive days) on amphetamine-induced locomotion and Fos expression as well as on FosB/ΔFosB-like immunoreactivity in mice of the C57BL/6J and DBA/2J inbred strains that differ for the response to amphetamine, stress and novelty. Daily experiences with the test cage increased FosB/ΔFosB-like immunoreactivity in the medial-prefrontal cortex of both strains of mice and in the caudate of mice of the C57 strain, as reported for repeated stress in the rat. Moreover, previous habituation to the test cage reduced the locomotor response to a low dose of amphetamine only in DBA mice while it reduced amphetamine-induced Fos expression in medial-prefrontal cortex, dorsal caudate and the accumbens shell of mice of the C57 strain. These results demonstrate indexes of stress-like plasticity in the brains of mice exposed to a procedure of familiarization to the testing environment. Moreover, they suggest that the procedure of daily familiarization influences the pattern of brain Fos expression induced by amphetamine. Finally, they indicate complex interactions between experience with the testing environment, genotype and drug.

Behavioral Depression: Opposite Effects of Neonatal Dexamethasone and ACTH-(4-9) Analogue (ORG 2766) Treatments in the Rat

Permanent changes in novelty-induced arousal and behavioral depression were studied in adult male Wistar rats having received sc injections of 1 μg/g body wt dexamethasone (DEX) or ACTH-(4-9) analogue (ORG 2766), or the combined treatment of these substances at Postnatal Days 1, 3, and 5. Treatment with DEX increased immobility in the Porsolt's water immersion and closed-field tests, delayed start latency, and attenuated orientation motility in an open-field, and enhanced defensive burying activity. On the contrary, the ACTH peptide caused more active behavior, resulted in an increased molility in the Porsolt's test, and decreased immobility in the closed-field chamber compared to controls. Behavioral reactivity of rats after combined DEX and ACTH peptide treatments was comparable to that of saline controls. The hormone treatments did not alter basal and stress-induced circulating corticosterone levels assessed at the adult age. The data suggest that neonatal DEX strengthens the development of brain mechanisms supporting behavioral depression in response to stressful situations, while ORG 2766 has principally an opposite effect and is able to compensate the longterm aberrant behavioral effects of neonatal DEX treatment.

Adrenocorticoid receptor binding in the rat hippocampus: strain-dependent covariations with arousal and habituation to novelty

In order to investigate whether the genotype-dependent behaviour of the Naples high-(NHE) and low-excitability (NLE) rat strains was modulated by differences in the capacity of hippocampal adrenocorticoid receptors, a correlative analysis was made among behavioural scores from exposure to a Làt-maze and in vitro [3H]corticosterone hippocampal binding capacity in these rats and in their random-bred controls (NRB). As previously shown, NHE/NLE-rats differed markedly upon forced exposure to the maze, with the NRB group occupying an intermediate position. No differences were found in maximal binding capacity (Bmax) and dissociation constant (Kd), nor in the individual maximal binding capacity (IMBC) between the two strains, while both showed lower IMBC than NRB-rats. These results tend to exclude that the genetic differences in the behaviour of NHE/NLE-rats are due to distinct patterns in the adrenocorticoid binding capacity in the hippocampus (HPC). Moreover, the intrastrain correlative analysis among IMBC (in the whole HPC and in its dorsal and ventral portion) and the behavioural scores showed that (1) motor and emotional correlates of 'arousal' to novelty were positively correlated in NLE and negatively in NHE-, but not in NRB-rats; (2) a consistent correlation was found with the intertrial activity decrement (long-term habituation), which was negative in both strains, and it was positive in NRB-rats. These complex co-variations are envisioned as possibly due to the differential modulatory components of the activation and inhibition of novelty-induced arousal response. However, our findings support the hypothesized involvement of the HPC, where adrenocorticoid receptors are selectively concentrated, in the modulation of some adaptive behavioural responses.