The Novel Analogue of Modafinil CE-158 Protects Social Memory against Interference and Triggers the Release of Dopamine in the Nucleus Accumbens of Mice.

Previous studies have shown that atypical dopamine-transporter-inhibitors such as modafinil and its analogues modify behavioral and cognitive functions in rodents. Here, we tested potential promnestic effects of the novel, more dopamine-transporter selective modafinil analogue CE-158 in the social discrimination memory task in male mice. Systemic administration of CE-158 1 h before the social learning event prevented the impairment of social-recognition memory following retroactive interference 3 h after the learning session of a juvenile conspecific. This effect was dose-dependent, as mice treated with 10 mg/kg, but not with 1 mg/kg CE-158, were able to discriminate between the novel and familiar conspecific despite the presentation of an interference stimulus, both 3 h and 6 h post learning. However, when 10 mg/kg of the drug was administered after learning, CE-158 failed to prevent social memory from interference. Paralleling these behavioral effects, the systemic administration of 10 mg/kg CE-158 caused a rapid and sustained elevation of extracellular dopamine in the nucleus accumbens, a brain area where dopaminergic signaling plays a key role in learning and memory function, of freely moving mice, while 1 mg/kg was not sufficient for altering dopamine levels. Taken together, our findings suggest promnestic effects of the novel dopamine-transporter-inhibitor CE-158 in a social recognition memory test that may be in part mediated via increased dopamine-neurotransmission in the nucleus accumbens. Thus, selective-dopamine-transporter-inhibitors such as CE-158 may represent interesting drug candidates for the treatment of memory complaints observed in humans with cognitive impairments and dementia.

Rescue of Vasopressin Synthesis in Magnocellular Neurons of the Supraoptic Nucleus Normalises Acute Stress-Induced Adrenocorticotropin Secretion and Unmasks an Effect on Social Behaviour in Male Vasopressin-Deficient Brattleboro Rats.

The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine stress axis and related behaviour is still under discussion. We aimed to obtain deeper insight into this process. To rescue magnocellular AVP synthesis, a vasopressin-containing adeno-associated virus vector (AVP-AAV) was injected into the supraoptic nucleus (SON) of AVP-deficient Brattleboro rats (di/di). We compared +/+, di/di, and AVP-AAV treated di/di male rats. The AVP-AAV treatment rescued the AVP synthesis in the SON both morphologically and functionally. It also rescued the peak of adrenocorticotropin release triggered by immune and metabolic challenges without affecting corticosterone levels. The elevated corticotropin-releasing hormone receptor 1 mRNA levels in the anterior pituitary of di/di-rats were diminished by the AVP-AAV-treatment. The altered c-Fos synthesis in di/di-rats in response to a metabolic stressor was normalised by AVP-AAV in both the SON and medial amygdala (MeA), but not in the central and basolateral amygdala or lateral hypothalamus. In vitro electrophysiological recordings showed an AVP-induced inhibition of MeA neurons that was prevented by picrotoxin administration, supporting the possible regulatory role of AVP originating in the SON. A memory deficit in the novel object recognition test seen in di/di animals remained unaffected by AVP-AAV treatment. Interestingly, although di/di rats show intact social investigation and aggression, the SON AVP-AAV treatment resulted in an alteration of these social behaviours. AVP released from the magnocellular SON neurons may stimulate adrenocorticotropin secretion in response to defined stressors and might participate in the fine-tuning of social behaviour with a possible contribution from the MeA.

Vasopressin and post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition with a wide range of behavioral disturbances and serious consequences for both patient and society. One of the main reasons for unsuccessful therapies is insufficient knowledge about its underlying pathomechanism. In the search for centrally signaling molecules that might be relevant to the development of PTSD we focus here on arginine vasopressin (AVP). So far AVP has not been strongly implicated in PTSD, but different lines of evidence suggest a possible impact of its signaling in all clusters of PTSD symptomatology. More specifically, in laboratory rodents, AVP agonists affect behavior in a PTSD-like manner, while significant reduction of AVP signaling in the brain e.g. in AVP-deficient Brattleboro rats, ameliorated defined behavioral parameters that can be linked to PTSD symptoms. Different animal models of PTSD also show alterations in the AVP signaling in distinct brain areas. However, pharmacological treatment targeting central AVP receptors via systemic routes is hampered by possible side effects that are linked to the peripheral action of AVP as a hormone. Indeed, the V1a receptor, the most common receptor subtype in the brain, is implicated in vasoconstriction. Thus, systemic treatment with V1a receptor antagonists would be implicated in hypotonia. This implies that novel treatment concepts are needed to target AVP receptors not only at brain level but also in distinct brain areas, to offer alternative treatments for PTSD.

Differential Effects of Novel Dopamine Reuptake Inhibitors on Interference With Long-Term Social Memory in Mice.

In the laboratory, long-term social recognition memory (SRM) in mice is highly susceptible to proactive and retroactive interference. Here, we investigate the ability of novel designed dopamine (DA) re-uptake inhibitors (rac-CE-123 and S-CE-123) to block retroactive and proactive interference, respectively. Our data show that administration of rac-CE-123 30 min before learning blocks retroactive interference that has been experimentally induced at 3 h, but not at 6 h, post-learning. In contrast, S-CE-123 treatment 30 min before learning blocked the induction of retroactive interference at 6 h, but not 3 h, post-learning. Administration of S-CE-123 failed to interfere with proactive interference at both 3 h and 6 h. Analysis of additional behavioral parameters collected during the memory task implies that the effects of the new DA re-uptake inhibitors on retroactive and proactive interference cannot easily be explained by non-specific effects on the animals' general social behavior. Furthermore, we assessed the mechanisms of action of drugs using intracerebral in vivo-microdialysis technique. The results revealed that administration of rac-CE-123 and S-CE-123 dose-dependently increased DA release within the nucleus accumbens of freely behaving mice. Thus, the data from the present study suggests that the DA re-uptake inhibitors tested protect the consolidation of long-term social memory against interference for defined durations after learning. In addition, the data implies that DA signaling in distinct brain areas including the nucleus accumbens is involved in the consolidation of SRM in laboratory mice.

Recognizing Others: Rodent's Social Memories.

We provide in this chapter a brief overview of the present knowledge about social memory in laboratory rodents with a focus on mice and rats. We discuss in the first part the relevance of the processing of olfactory cues for social recognition in these animals and present information about the brain areas involved in the generation of a long-term social memory including cellular mechanisms thought to underlie memory consolidation. In the second part, we suggest that sensory modalities beyond olfaction may also be important in contributing to the long-term social memory trace including audition and taction (and vision). The exposure to stimuli activating the auditory system and taction is able to produce interference phenomena at defined time points during the consolidation of social memory. This ability of such-nonsocial-stimuli may provide a new approach to dissect the brain processes underlying the generation of the social memory trace in further studies.

Vasopressinergic control of stress-related behavior: studies in Brattleboro rats.

Vasopressin, a nonapeptide, signaling both as hormone in the blood and neuromodulator/neurotransmitter in the brain is considered to be causally involved in the pathological changes underlying anxiety and depression. In the present review we summarize experimental data obtained with Brattleboro rats as a model of congenital vasopressin-deficiency to test the hypothesis that central vasopressin signaling contributes to anxiety- and depression-like behavior. Male, female and lactating rats were studied. We focused on the paraventricular nucleus of the hypothalamus (PVN) and the septum, two brain areas in which vasopressin is proposed to control the endocrine and behavioral stress response, respectively. The presented data support the hypothesis that the behavioral changes seen in these rats are brought about by an altered vasopressin signaling at the brain level. Whereas vasopressin synthesized and released within the hypothalamus is primarily involved in endocrine regulation, vasopressin signaling in other brain areas may contribute to anxiety- and depression-like behavioral parameters. Further studies in this context might focus particularly on the interplay between extra-hypothalamic brain areas such as the septum and the medial amygdala.

Vasopressin signaling at brain level controls stress hormone release: the vasopressin-deficient Brattleboro rat as a model.

The nonapeptide arginine vasopressin (AVP) has long been suggested to play an important role as a secretagogue for triggering the activity of the endocrine stress response. Most recent studies employed mutant mice for analyzing the importance of AVP for endocrine regulation under stress. However, it is difficult to compare and draw overall conclusions from all these studies as mixing the genetic material from different mouse strains has consequences on the individual's stress response. Moreover, mice are not ideal subjects for several experimental procedures. Therefore, to get more insight, we used a rather old mutant rat model: the AVP-deficient Brattleboro rat. The present short review is aimed at providing the most interesting results of these studies within the last 8 years that allowed gaining new insights in the potential signal function of AVP in stress and endocrine regulation.

Consequences of temporary inhibition of the medial amygdala on social recognition memory performance in mice.

Different lines of investigation suggest that the medial amygdala is causally involved in the processing of information linked to social behavior in rodents. Here we investigated the consequences of temporary inhibition of the medial amygdala by bilateral injections of lidocaine on long-term social recognition memory as tested in the social discrimination task. Lidocaine or control NaCl solution was infused immediately before learning or before retrieval. Our data show that lidocaine infusion immediately before learning did not affect long-term memory retrieval. However, intra-amygdalar lidocaine infusions immediately before choice interfered with correct memory retrieval. Analysis of the aggressive behavior measured simultaneously during all sessions in the social recognition memory task support the impression that the lidocaine dosage used here was effective as it-at least partially-reduced the aggressive behavior shown by the experimental subjects toward the juveniles. Surprisingly, also infusions of NaCl solution blocked recognition memory at both injection time points. The results are interpreted in the context of the importance of the medial amygdala for the processing of non-volatile odors as a major contributor to the olfactory signature for social recognition memory.

Timing of presentation and nature of stimuli determine retroactive interference with social recognition memory in mice.

The present study was designed to further investigate the nature of stimuli and the timing of their presentation, which can induce retroactive interference with social recognition memory in mice. In accordance with our previous observations, confrontation with an unfamiliar conspecific juvenile 3h and 6h, but not 22 h, after the initial learning session resulted in retroactive interference. The same effect was observed with the exposure to both enantiomers of the monomolecular odour carvone, and with a novel object. Exposure to a loud tone (12 KHz, 90 dB) caused retroactive interference at 6h, but not 3h and 22 h, after sampling. Our data show that retroactive interference of social recognition memory can be induced by exposing the experimental subjects to the defined stimuli presented <22 h after learning in their home cage. The distinct interference triggered by the tone presentation at 6h after sampling may be linked to the intrinsic aversiveness of the loud tone and suggests that at this time point memory consolidation is particularly sensitive to stress.

Restoration of peripheral V2 receptor vasopressin signaling fails to correct behavioral changes in Brattleboro rats.

Beside its hormonal function in salt and water homeostasis, vasopressin released into distinct brain areas plays a crucial role in stress-related behavior resulting in the enhancement of an anxious/depressive-like state. We aimed to investigate whether correction of the peripheral symptoms of congenital absence of AVP also corrects the behavioral alterations in AVP-deficient Brattleboro rats. Wild type (WT) and vasopressin-deficient (KO) male Brattleboro rats were tested. Half of the KO animals were treated by desmopressin (V2-receptor agonist) via osmotic minipump (subcutaneous) to eliminate the peripheral symptoms of vasopressin-deficiency. Anxiety was studied by elevated plus maze (EPM), defensive withdrawal (DW) and marble burying (MB) tests, while depressive-like changes were monitored in forced swimming (FS) and anhedonia by sucrose preference test. Cell activity was examined in septum and amygdala by c-Fos immunohistochemistry after 10 min FS. KO rats spent more time in the open arm of the EPM, spent less time at the periphery of DW and showed less burying behavior in MB suggesting a reduced anxiety state. KO animals showed less floating behavior during FS revealing a less depressive phenotype. Desmopressin treatment compensated the peripheral effects of vasopressin-deficiency without a significant influence on the behavior. The FS-induced c-Fos immunoreactivity in the medial amygdala was different in WT and KO rats, with almost identical levels in KO and desmopressin treated animals. There were no differences in central and basolateral amygdala as well as in lateral septum. Our data confirmed the role of vasopressin in the development of affective disorders through central mechanisms. The involvement of the medial amygdala in the behavioral alterations of vasopressin deficient animals deserves further attention.

Blunted HPA axis response in lactating, vasopressin-deficient Brattleboro rats.

Adaptation to stress is a basic phenomenon in mammalian life that is mandatorily associated with the activity of the hypothalamic-pituitary-adrenal (HPA) axis. An increased resting activity of the HPA axis can be measured during pregnancy and lactation, suggesting that these reproductive states lead to chronic load in females. In this study, we examined the consequences of the congenital lack of vasopressin on the activity of the HPA axis during lactation using vasopressin-deficient Brattleboro rats. Virgin and lactating, homozygous vasopressin-deficient rats were compared with control, heterozygous rats. In control dams compared with virgins, physiological changes similar to those observed in a chronic stress state (thymus involution, adrenal gland hyperplasia, elevation of proopiomelanocortin mRNA levels in the adenohypophysis, and resting plasma corticosterone levels) were observed. In vasopressin-deficient dams, adrenal gland hyperplasia and resting corticosterone level elevations were not observed. Corticotropin-releasing hormone (Crh) mRNA levels in the hypothalamic paraventricular nucleus were elevated in only the control dams, while oxytocin (OT) mRNA levels were higher in vasopressin-deficient virgins and lactation induced a further increase in both the genotypes. Suckling-induced ACTH and corticosterone level elevations were blunted in vasopressin-deficient dams. Anaphylactoid reaction (i.v. egg white) and insulin-induced hypoglycemia stimulated the HPA axis, which were blunted in lactating rats compared with the virgins and in vasopressin-deficient rats compared with the controls without interaction of the two factors. Vasopressin seems to contribute to the physiological changes observed during lactation mimicking a chronic stress state, but its role in acute HPA axis regulation during lactation seems to be similar to that observed in virgins. If vasopressin is congenitally absent, OT, but not the CRH, compensates for the missing vasopressin; however, the functional restitution remains incomplete.

Social investigation and long-term recognition memory performance in 129S1/SvImJ and C57BL/6JOlaHsd mice and their hybrids.

When tested for their behavioural performance, the mixed genetic background of transgenic mice is a critical, but often ignored, issue. Such issues can arise because of the significant differences in defined behavioural parameters between embryonic stem cell donor and recipient strains. In this context, the commonly used stem cell donor strain '129' shows 'deficits' in different paradigms for learning and long-term memory. We investigated the long-term social recognition memory performance and the investigative behaviour in commercially available 129S1/SvImJ and C57BL/6JOlaHsd mice and two F1-hybrids (129S1/SvImJ×C57BL/6JOlaHsd) by using the social discrimination procedure and its modification, the volatile fraction cage (VFC). Our data revealed an unimpaired olfactory long-term recognition memory not only in female and male 129S1/SvImJ and C57BL/6JOlaHsd mice but also in the two hybrid lines (129S1/SvImJxC57BL/6JOlaHsd) when the full 'olfactory signature' of the 'to-be-recognized' conspecific was presented. Under these conditions we also failed to detect differences in the long-term recognition memory between male and female mice of the tested strains and revealed that the oestrus cycle did not affect the performance in this memory task. The performance in the VFC, based only on the volatile components of the 'olfactory signature' of the 'to-be-recognized' conspecific, was similar to that observed under direct exposure except that females of one F1 hybrid group failed to show an intact long-term memory. Thus, the social discrimination procedure allowing direct access between the experimental subject and the stimulus animal(s) is highly suitable to investigate the impact of genetic manipulations on long-term memory in male and female mice of the strain 129S1/SvImJ, C57BL/6JOlaHsd and 129S1/SvImJxC57BL/6JOlaHsd hybrids.

Testing declarative memory in laboratory rats and mice using the nonconditioned social discrimination procedure.

Testing declarative memory in laboratory rodents can provide insights into the fundamental mechanisms underlying this type of learning and memory processing, and these insights are likely to be applicable to humans. Here we provide a detailed description of the social discrimination procedure used to investigate recognition memory in rats and mice, as established during the last 20 years in our laboratory. The test is based on the use of olfactory signals for social communication in rodents; this involves a direct encounter between conspecifics, during which the investigatory behavior of the experimental subject serves as an index for learning and memory performance. The procedure is inexpensive, fast and very reliable, but it requires well-trained human observers. We include recent modifications to the procedure that allow memory extinction to be investigated by retroactive and proactive interference, and that enable the dissociated analysis of the central nervous processing of the volatile fraction of an individual's olfactory signature. Depending on the memory retention interval under study (short-term memory, intermediate-term memory, long-term memory or long-lasting memory), the protocol takes ~10 min or up to several days to complete.

Vasopressin and social odor processing in the olfactory bulb and anterior olfactory nucleus.

Central vasopressin facilitates social recognition and modulates numerous complex social behaviors in mammals, including parental behavior, aggression, affiliation, and pair-bonding. In rodents, social interactions are primarily mediated by the exchange of olfactory information, and there is evidence that vasopressin signaling is important in brain areas where olfactory information is processed. We recently discovered populations of vasopressin neurons in the main and accessory olfactory bulbs and anterior olfactory nucleus that are involved in the processing of social odor cues. In this review, we propose a model of how vasopressin release in these regions, potentially from the dendrites, may act to filter social odor information to facilitate odor-based social recognition. Finally, we discuss recent human research linked to vasopressin signaling and suggest that our model of priming-facilitated vasopressin signaling would be a rewarding target for further studies, as a failure of priming may underlie pathological changes in complex behaviors.

Different importance of the volatile and non-volatile fractions of an olfactory signature for individual social recognition in rats versus mice and short-term versus long-term memory.

When tested in the olfactory cued social recognition/discrimination test, rats and mice differ in their retention of a recognition memory for a previously encountered conspecific juvenile: Rats are able to recognize a given juvenile for approximately 45 min only whereas mice show not only short-term, but also long-term recognition memory (≥ 24 h). Here we modified the social recognition/social discrimination procedure to investigate the neurobiological mechanism(s) underlying the species differences. We presented a conspecific juvenile repeatedly to the experimental subjects and monitored the investigation duration as a measure for recognition. Presentation of only the volatile fraction of the juvenile olfactory signature was sufficient for both short- and long-term recognition in mice but not rats. Applying additional volatile, mono-molecular odours to the "to be recognized" juveniles failed to affect short-term memory in both species, but interfered with long-term recognition in mice. Finally immunocytochemical analysis of c-Fos as a marker for cellular activation, revealed that juvenile exposure stimulated areas involved in the processing of olfactory signals in both the main and the accessory olfactory bulb in mice. In rats, we measured an increased c-Fos synthesis almost exclusively in cells of the accessory olfactory bulb. Our data suggest that the species difference in the retention of social recognition memory is based on differences in the processing of the volatile versus non-volatile fraction of the individuals' olfactory signature. The non-volatile fraction is sufficient for retaining a short-term social memory only. Long-term social memory - as observed in mice - requires a processing of both the volatile and non-volatile fractions of the olfactory signature.

Expression of early growth response protein 1 in vasopressin neurones of the rat anterior olfactory nucleus following social odour exposure.

The anterior olfactory nucleus (AON), a component of the main olfactory system, is a cortical region that processes olfactory information and acts as a relay between the main olfactory bulbs and higher brain regions such as the piriform cortex. Utilizing a transgenic rat in which an enhanced green fluorescent protein reporter gene is expressed in vasopressin neurones (eGFP-vasopressin), we have discovered a population of vasopressin neurones in the AON. These vasopressin neurones co-express vasopressin V1 receptors. They also co-express GABA and calbinin-D28k indicating that they are neurochemically different from the newly described vasopressin neurons in the main olfactory bulb. We utilized the immediate early gene product, early growth response protein 1 (Egr-1), to examine the functional role of these vasopressin neurons in processing social and non-social odours in the AON. Exposure of adult rats to a conspecific juvenile or a heterospecific predator odour leads to increases in Egr-1 expression in the AON in a subregion specific manner. However, only exposure to a juvenile increases Egr-1 expression in AON vasopressin neurons. These data suggest that vasopressin neurones in the AON may be selectively involved in the coding of social odour information.

An intrinsic vasopressin system in the olfactory bulb is involved in social recognition.

Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader-Willi syndrome, affective disorders and obsessive-compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.

Urocortin 1 administered into the hypothalamic supraoptic nucleus affects open-field behaviour in rats.

The presence of both Urocortin 1 (Ucn1) and corticotropin-releasing factor 2 receptors (CRF(2)R) in the hypothalamic supraoptic nucleus (SON) suggests that endogenous Ucn1 released within this brain area acts as a local signal that might be involved in the regulation of not only endocrine but also behavioural stress responses. To test this hypothesis, we monitored the effects induced by the administration of a range of doses of synthetic Ucn1 (0.001-1.0 microg) bilaterally into the SON of rats in the open field test (OFT). Ucn1 administration produced an inverted U-shaped dose-response curve on OFT behaviour, in particular the dose of 0.01 microg of Ucn1 significantly increased the number of rearing and grooming episodes without affecting locomotion. In addition, this dosage augmented also the latency to visit the centre of the open field. Pre-treatment with the CRF(2)R antagonist, astressin-2B (0.1 microg) normalized Ucn1 treatment-induced effects. These results suggest that Ucn1 released within the SON area interacts with CRF(2)R to control the state of arousal.

High-resolution mapping of neuronal activity using the lipophilic thallium chelate complex TlDDC: protocol and validation of the method.

In neurons the rate of K(+)-uptake increases with increasing activity. K(+)-analogues like the heavy metal ion thallium (Tl(+)) can be used, therefore, as tracers for imaging neuronal activity. However, when water-soluble Tl(+)-salts are injected systemically only minute amounts of the tracer enter the brain and the Tl(+)-uptake patterns are influenced by regional differences in blood-brain barrier (BBB) K(+)-permeability. We here show that the BBB-related limitations in using Tl(+) for imaging neuronal activity are no longer present when the lipophilic Tl(+) chelate complex thallium diethyldithiocarbamate (TlDDC) is applied. We systemically injected rodents with TlDDC and mapped the Tl(+)-distribution in the brain using an autometallographic (AMG) technique, a histochemical method for detecting heavy metals. We find that Tl(+)-doses for optimum AMG staining could be substantially reduced, and regional differences attributable to differences in BBB K(+)-permeability were no longer detectable, indicating that TlDDC crosses the BBB. At the cellular level, however, the Tl(+)-distribution was essentially the same as after injection of water-soluble Tl(+)-salts, indicating Tl(+)-release from TlDDC prior to neuronal or glial uptake. Upon sensory stimulation or intracortical microstimulation neuronal Tl(+)-uptake increased after TlDDC injection, upon muscimol treatment neuronal Tl(+)-uptake decreased. We present a protocol for mapping neuronal activity with cellular resolution, which is based on intravenous TlDDC injections during ongoing activity in unrestrained behaving animals and short stimulation times of 5 min.

Congenital lack of nNOS impairs long-term social recognition memory and alters the olfactory bulb proteome.

The gaseous neurotransmitter nitric oxide (NO), synthesized by the enzyme neuronal nitric oxide synthase (nNOS), is thought to play a major role in the modulation of memory. We tested adult nNOS-deficient and wild-type mice for their recognition memory abilities in the social discrimination paradigm, which is based on olfactory cues. Subsequently, proteomic investigation of the olfactory bulbs of both genotypes were performed under basal conditions and 6 h after learning, i.e., during the consolidation of long-term memory. Short-term and intermediate-term recognition memory was normal in nNOS-deficient mice. However, unlike wild-type mice, nNOS-deficient mice failed to consolidate an olfactory cued long-term recognition memory. Proteomic analysis revealed changes in glycolytic enzymes (e.g., fructose-bisphosphate aldolase C, glyceraldehyde-3-phosphate dehydrogenase), voltage-dependent anion-selective channels 1 and 2, alpha-synuclein, F-actin-interacting proteins (e.g., neuronal protein 25/transgelin 3), proteins of the ubiquitin proteasome system, and heterogeneous nuclear ribonucleoproteins implicated in the regulation of messenger RNA trafficking, stability and translation. Our data suggest that, in the mouse, NO of nNOS origin is critically involved in the regulation of protein synthesis-dependent olfactory long-term memory consolidation within relevant brain structures including the olfactory bulb.