Participation of Hippocampal 5-HT5A, 5-HT6 and 5-HT7 Serotonin Receptors on the Consolidation of Social Recognition Memory.

Social recognition is the ability of animals to identify and recognize a conspecific. The consolidation of social stimuli in long-term memory is crucial for the establishment and maintenance of social groups, reproduction and species survival. Despite its importance, little is known about the circuitry and molecular mechanisms involved in the social recognition memory (SRM). Serotonin (5-hydroxytryptamine, 5-HT) is acknowledged as a major neuromodulator, which plays a key role in learning and memory. Focusing on the more recently described 5-HT receptors, we investigated in the CA1 region of the dorsal hippocampus the participation of 5-HT5A, 5-HT6 and 5-HT7 receptors in the consolidation of SRM. Male Wistar rats cannulated in CA1 were subjected to a social discrimination task. In the sample phase the animals were exposed to a juvenile conspecific for 1 h. Immediately after, they received different pharmacological treatments. Twenty-four hours later, they were submitted to a 5 min retention test in the presence of the previously presented juvenile (familiar) and a novel juvenile. The animals that received infusions of 5-HT5A receptor antagonist SB-699551 (10 µg/µL), 5-HT6 receptor agonist WAY-208466 (0.63 µg/µL) or 5-HT7 receptor agonist AS-19 (5 µg/µL) intra-CA1 were unable to recognize the familiar juvenile. This effect was blocked by the coinfusion of WAY-208466 plus 5-HT6 receptor antagonist SB-271046 (10 µg/µL) or AS-19 plus 5-HT7 receptor antagonist SB-269970 (5 µg/µL). The present study helps to clarify the neurobiological functions of the 5-HT receptors more recently described and extends our knowledge about mechanisms underlying the SRM.

Modulation of Carbonic Anhydrases Activity in the Hippocampus or Prefrontal Cortex Differentially Affects Social Recognition Memory in Rats.

Growing evidence indicates that brain carbonic anhydrases (CAs) are key modulators in cognition, particularly in recognition and aversive memories. Here we described a role for these enzymes also in social recognition memory (SRM), defined as the ability to identify and recognize a conspecific, a process that is of paramount importance in gregarious species, such as rodents and humans. Male adult Wistar rats were submitted to a social discrimination task and, immediately after the sample phase, received bilateral infusions of vehicle, the CAs activator D-phenylalanine (D-Phen, 50 nmols/side), the CAs inhibitor acetazolamide (ACTZ; 10 nmols/side) or the combination of D-Phen and ACTZ directly in the CA1 region of the dorsal hippocampus or in the medial prefrontal cortex (mPFC). Animals were tested 30 min (short-term memory) or 24 h later (long-term memory). We found that inhibition of CAs with infusion of ACTZ either in the CA1 or in the mPFC impaired short-term SRM and that this effect was completely abolished by the combined infusion of D-Phen and ACTZ. We also found that activation of CAs with D-Phen facilitated the consolidation of long-term SRM in the mPFC but not in CA1. Finally, we show that activation of CAs in CA1 and in the mPFC enhances the persistence of SRM for up to 7 days. In both cases, the co-infusion of ACTZ fully prevented D-Phen-induced procognitive effects. These results suggest that CAs are key modulators of SRM and unveil a differential involvement of these enzymes in the mPFC and CA1 on memory consolidation.

Inhibition of PACAP/PAC1/VPAC2 signaling impairs the consolidation of social recognition memory and nitric oxide prevents this deficit.

Social recognition memory (SRM) forms the basis of social relationships of animals. It is essential for social interaction and adaptive behavior, reproduction and species survival. Evidence demonstrates that social deficits of psychiatric disorders such as autism and schizophrenia are caused by alterations in SRM processing by the hippocampus and amygdala. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptors PAC1, VPAC1 and VPAC2 are highly expressed in these regions. PACAP is a pleiotropic neuropeptide that modulates synaptic function and plasticity and is thought to be involved in social behavior. PACAP signaling also stimulates the nitric oxide (NO) production and targets outcomes to synapses. In the present work, we investigate the effect of the infusion of PACAP-38 (endogenous neuropeptide and potent stimulator of adenylyl cyclase), PACAP 6-38 (PAC1/VPAC2 receptors antagonist) and S-Nitroso-N-acetyl-DL-penicillamine (SNAP, NO donor) in the CA1 region of the hippocampus and in the basolateral amygdala (BLA) on the consolidation of SRM. For this, male Wistar rats with cannulae implanted in CA1 or in BLA were subjected to a social discrimination paradigm, which is based on the natural ability of rodents to investigate unfamiliar conspecifics more than familiar one. In the sample phase (acquisition), animals were exposed to a juvenile conspecific for 1 h. Immediately, 60 or 150 min after, animals received one of different pharmacological treatments. Twenty-four hours later, they were submitted to a 5 min retention test in the presence of the previously presented juvenile (familiar) and a novel juvenile. Animals that received infusions of PACAP 6-38 (40 pg/side) into CA1 immediately after the sample phase or into BLA immediately or 60 min after the sample phase were unable to recognize the familiar juvenile during the retention test. This impairment was abolished by the coinfusion of PACAP 6-38 plus SNAP (5 µg/side). These results show that the blockade of PACAP/PAC1/VPAC2 signaling in the CA1 and BLA during a restricted post-acquisition time window impairs the consolidation of SRM and that the SNAP is able to abolish this deficit. Findings like this could potentially be used in the future to influence studies of psychiatric disorders involving social behavior.

The role of carbonic anhydrases in extinction of contextual fear memory.

Carbonic anhydrases (CAs; EC 4.2.1.1) are metalloenzymes present in mammals with 16 isoforms that differ in terms of catalytic activity as well as cellular and tissue distribution. CAs catalyze the conversion of CO2 to bicarbonate and protons and are involved in various physiological processes, including learning and memory. Here we report that the integrity of CA activity in the brain is necessary for the consolidation of fear extinction memory. We found that systemic administration of acetazolamide, a CA inhibitor, immediately after the extinction session dose-dependently impaired the consolidation of fear extinction memory of rats trained in contextual fear conditioning. d-phenylalanine, a CA activator, displayed an opposite action, whereas C18, a membrane-impermeable CA inhibitor that is unable to reach the brain tissue, had no effect. Simultaneous administration of acetazolamide fully prevented the procognitive effects of d-phenylalanine. Whereas d-phenylalanine potentiated extinction, acetazolamide impaired extinction also when infused locally into the ventromedial prefrontal cortex, basolateral amygdala, or hippocampal CA1 region. No effects were observed when acetazolamide or d-phenylalanine was infused locally into the substantia nigra pars compacta. Moreover, systemic administration of acetazolamide immediately after the extinction training session modulated c-Fos expression on a retention test in the ventromedial prefrontal cortex of rats trained in contextual fear conditioning. These findings reveal that the engagement of CAs in some brain regions is essential for providing the brain with the resilience necessary to ensure the consolidation of extinction of emotionally salient events.

Preventing adolescent stress-induced cognitive and microbiome changes by diet.

Psychological stress during adolescence may cause enduring cognitive deficits and anxiety in both humans and animals, accompanied by rearrangement of numerous brain structures and functions. A healthy diet is essential for proper brain development and maintenance of optimal cognitive functions during adulthood. Furthermore, nutritional components profoundly affect the intestinal community of microbes that may affect gut-brain communication. We adopted a relatively mild stress protocol, social instability stress, which when repeatedly administered to juvenile rats modifies cognitive behaviors and plasticity markers in the brain. We then tested the preventive effect of a prolonged diet enriched with the ω-3 polyunsaturated fatty acids eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid and vitamin A. Our findings highlight the beneficial effects of this enriched diet on cognitive memory impairment induced by social instability stress, as stressed rats fed the enriched diet exhibited performance undistinguishable from that of nonstressed rats on both emotional and reference memory tests. Furthermore, in stressed rats, the decline in brain-derived neurotrophic factor expression in the hippocampus and shifts in the microbiota composition were normalized by the enriched diet. The detrimental behavioral and neurochemical effects of adolescent stress, as well as the protective effect of the enriched diet, were maintained throughout adulthood, long after the exposure to the stressful environment was terminated. Taken together, our results strongly suggest a beneficial role of nutritional components in ameliorating stress-related behaviors and associated neurochemical and microbiota changes, opening possible new venues in the field of nutritional neuropsychopharmacology.

Methylphenidate induces state-dependency of social recognition learning: Central components.

Methylphenidate (MPH) is a widely prescribed drug for the treatment of attention-deficit hyperactivity disorder. Findings in the literature suggest that the effects of MPH on memory may result from increased extracellular levels of norepinephrine (NE) and dopamine (DA). Here, we report that the systemic administration of MPH before the acquisition phase in a social discrimination task impaired the retrieval of the social recognition memory (SRM), but made it state-dependent: another administration of MPH before the retention test recovered the SRM. We observed that the induction of state dependency by MPH relies on the ventromedial prefrontal cortex (vmPFC), but not on the CA1 region of the hippocampus (CA1). Also, the inhibitors of NE and DA, nisoxetine and GBR12909, respectively, restored the SRM when infused into the vmPFC. Only the GBR12909 was able to restore the SRM in the CA1, whereas nisoxetine could not restore and even caused an impairment on memory retrieval when infused alone before the retention test. The data suggest that the state-dependence of SRM induced by MPH depends on an influence of both catecholamines on the vmPFC, while NE inhibits the retrieval of SRM on the hippocampus.

Carbonic anhydrase activation enhances object recognition memory in mice through phosphorylation of the extracellular signal-regulated kinase in the cortex and the hippocampus.

Rats injected with by d-phenylalanine, a carbonic anhydrase (CA) activator, enhanced spatial learning, whereas rats given acetazolamide, a CA inhibitor, exhibited impairments of fear memory consolidation. However, the related mechanisms are unclear. We investigated if CAs are involved in a non-spatial recognition memory task assessed using the object recognition test (ORT). Systemic administration of acetazolamide to male CD1 mice caused amnesia in the ORT and reduced CA activity in brain homogenates, while treatment with d-phenylalanine enhanced memory and increased CA activity. We provided also the first evidence that d-phenylalanine administration rapidly activated extracellular signal-regulated kinase (ERK) pathways, a critical step for memory formation, in the cortex and the hippocampus, two brain areas involved in memory processing. Effects elicited by d-phenylalanine were completely blunted by co-administration of acetazolamide, but not of 1-N-(4-sulfamoylphenyl-ethyl)-2,4,6-trimethylpyridinium perchlorate (C18), a CA inhibitor that, differently from acetazolamide, does not cross the blood brain barrier. Our results strongly suggest that brain but not peripheral CAs activation potentiates memory as a result of ERK pathway enhanced activation.