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Structural synaptic changes have been suggested to underlie long-term memory formation. In this work, we investigate if hippocampal mossy fiber synaptogenesis induced by water maze overtraining can be related with long-term spatial memory performance. Rats were trained in a Morris water maze for one to five identical daily sessions and tested for memory retrieval 1 week and 1 month after training. After the last test session, the rat brains were obtained and processed for Timm's staining to analyze mossy fiber projection. The behavioral results showed that with more training, animals showed a better performance in the memory tests, and this performance positively correlates with Timm's staining in the stratum oriens. Furthermore, with the use of the NMDA antagonist MK801 before, but not after acquisition, water maze spatial memory was impaired. Increased Timm's staining in the stratum oriens was observed in the animals treated with MK801 after acquisition but not in those treated before. Finally, we observed that mossy fiber synaptogenesis occurs mainly in the septal region of the dorsal hippocampus, supporting the idea that this anterior region is important for spatial memory. Altogether, these results suggest that mossy fiber synaptogenesis can be related with spatial long-term memory formation.

It is demonstrated that acetylcholine released from cholinergic interneurons modulates the excitability of neostriatal projection neurons. Physostigmine and neostigmine increase input resistance (RN) and enhance evoked discharge of spiny projection neurons in a manner similar to muscarine. Muscarinic RN increase occurs in the whole subthreshold voltage range (-100 to -45 mV), remains in the presence of TTX and Cd2+, and can be blocked by the relatively selective M1,4 muscarinic receptor antagonist pirenzepine but not by M2 or M3 selective antagonists. Cs+ occludes muscarinic effects at potentials more negative than -80 mV. A Na+ reduction in the bath occludes muscarinic effects at potentials more positive than -70 mV. Thus, muscarinic effects involve different ionic conductances: inward rectifying and cationic. The relatively selective M2 receptor antagonist AF-DX 116 does not block muscarinic effects on the projection neuron but, surprisingly, has the ability to mimic agonistic actions increasing RN and firing. Both effects are blocked by pirenzepine. HPLC measurements of acetylcholine demonstrate that AF-DX 116 but not pirenzepine greatly increases endogenous acetylcholine release in brain slices. Therefore, the effects of the M2 antagonist on the projection neurons were attributable to autoreceptor block on cholinergic interneurons. These experiments show distinct opposite functions of muscarinic M1- and M2-type receptors in neostriatal output, i.e., the firing of projection neurons. The results suggest that the use of more selective antimuscarinics may be more profitable for the treatment of motor deficits.

Conditioned taste aversion (CTA) is a learning paradigm in which an animal avoids a taste (conditioned stimulus) previously associated with visceral toxic effects [or unconditioned stimulus (US)]. Although many studies have implicated glutamate-mediated neurotransmission in memory consolidation of different types of learning tasks, including CTA, the exact role of this neurotransmitter system in memory formation is not known. Thus, we set out to determine whether glutamate mediates signaling of the US in CTA. We present evidence obtained by in vivo microdialysis that the US (i.p. injection of lithium chloride) induced a dramatic increase in glutamate release in the amygdala and a modest but significant release in the insular cortex. Moreover, CTA can be elicited by intra-amygdalar microinjections of glutamate; consequently, when glutamate is administered just before the presentation of a weak US, a clear CTA is induced. In contrast, the injection of glutamate alone or glutamate 2 h after the suboptimal US did not have any effect on the acquisition of CTA. These results indicate that glutamate activation of the amygdala can partially substitute the US in CTA, thus providing a clear indication that the amygdala conveys visceral information for this kind of memory.A number of studies (1-5) have implicated glutamatemediated transmission in consolidation of memory for different types of training, such as inhibitory avoidance, Morris water maze, and conditioned taste aversion (CTA). CTA is a learning paradigm in which the novel taste of food or drink (conditioned stimulus, CS) is paired with visceral signals of poisoning (unconditioned stimulus, US). Consequently, the animals avoid consuming the food or drink previously associated with toxic effects. CTA has unique properties; it is established after a single trial, permits long delays between stimuli presentation, and lasts for very long periods of time, even weeks. This feature makes it possible to separate the acquisition process into phases-CS presentation and US presentation-which can be studied independently under different experimental treatments (6).CTA is established by the interaction of brainstem, limbic, and neocortical structures underlying different phases of the acquisition storage and retrieval of gustatory memory (7). Among the structures involved in the initial phases of taste memory formation are the gustatory neocortex and amygdala (8). Thus, damage to either the gustatory insular cortex (IC) or amygdala in adult rats leads to impaired acquisition of CTA (6,7,[9][10][11][12][13][14][15][16][17]. However, the functional roles of IC and amygdala seem to be different during the phases of taste memory formation. Functional blockade of IC before taste presentation, but not between taste presentation and lithium chloride (LiCl) injection, blocks CTA (16, 18), suggesting that the gustatory cortex is involved in taste processing and͞or memory but is not necessary for processing the visceral signals of poisoning. Conversely, amygdala functional inactivation...

Glucocorticoids and corticotropin-releasing hormone (CRH) are key regulators of stress responses. Different types of stress activate the CRH system; in hypothalamus, CRH expression and release are increased by physical or psychological stressors while in amygdala, preferentially by psychological stress. Learning and memory processes are modulated by glucocorticoids and stress at different levels. To characterize the kind of stress provoked by a hippocampal-dependent task such as spatial learning, we compared the expression profile of glucocorticoid receptor (GR), pro-CRH and CRH-R1 mRNAs (analyzed by RT-PCR), in amygdala, hippocampus and hypothalamus and quantified serum corticosterone levels by radioimmunoassay at different stages of training. mRNA levels of brain-derived neurotrophic factor (BDNF) were also quantified due to its prominent role in learning and memory processes. Male Wistar rats trained for 1, 3 or 5 days in the Morris water-maze (10 trials/day) were sacrificed 5–60 min the after last trial. A strong stress response occurred at day one in both yoked and trained animals (increased corticosterone and hypothalamic pro-CRH and CRH-R1 mRNA levels); changes gradually diminished as the test progressed. In amygdala, pro-CRH mRNA levels decreased while those of BDNF augmented when stress was highest, in yoked and trained animals. Hippocampi, of both yoked and trained groups, had decreased levels of GR mRNA on days 1 and 3, normalizing by day 5, while those of pro-CRH and CRH-R1 increased after the 3rd day. Increased gene expression, specifically due to spatial learning, occurred only for hippocampal BDNF since day 3. These results show that the Morris water-maze paradigm induces a strong stress response that is gradually attenuated. Inhibition of CRH expression in amygdala suggests that the stress inflicted is of physical but not of psychological nature and could lead to reduced fear or anxiety.

Previous findings indicate that the acquisition and consolidation of recognition memory involves dopaminergic activity. Although dopamine deregulation has been observed in Alzheimer's disease (AD) patients, the dysfunction of this neurotransmitter has not been investigated in animal models of AD. The aim of this study was to assess, by in vivo microdialysis, cortical and hippocampal dopamine, norepinephrine, and glutamate release during the acquisition of object recognition memory (ORM) in 5-and 10-mo-old triple-transgenic Alzheimer's disease mice (3xTg-AD) and to relate the extracellular changes to 24-h memory performance. Five-and 10-mo-old wild-type mice and 5-mo-old 3xTg-AD showed significant cortical but not hippocampal dopamine increase during object exploration. On a 24-h ORM test, these three groups displayed significant ORM. In contrast, 10-mo-old 3xTg-AD mice showed impaired dopamine release in the insular cortex during ORM acquisition, as well as significant impairment in ORM. In addition, cortical administration of a dopamine reuptake blocker produced an increase of dopamine levels in the 10-mo-old 3xTg-AD mice and attenuated the memory impairment. These data suggest that activation of the dopaminergic system in the insular cortex is involved in object recognition memory, and that dysfunction of this system contributes to the age-related decline in cognitive functioning of the 3xTg-AD mice.Alzheimer's disease (AD) is an age-related and progressive degenerative disorder generally characterized by two neuropathological features: deposits of amyloid-beta (Ab) peptides and neurofibrillary tangles, formed by the hyperphosphorylated microtubulebinding protein tau (Selkoe 2001). These neuropathological features are generally prominent in learning and memory-related brain regions, including the hippocampus, amygdala, and neocortex (Braak and Braak 1991;Nicholson et al. 2010). Because these pathologies are related to synaptic dysfunction leading to neurotransmitter deregulation including acetylcholine deficiency (Davis et al. 1999), several pharmacological therapies for AD focus on the restoration or modulation of cholinergic neurotransmission by acetylcholinesterase inhibitors and muscarinic agonists (Caccamo et al. 2009;Galluzzi et al. 2010). However, there is also evidence that these treatments may increase extracellular levels of dopamine (DA) (Shearman et al. 2006;Preda et al. 2008), suggesting that DA increase may contribute to the therapeutic effect. The possibility that the dopaminergic system may be involved in AD is suggested by evidence of decreased DA levels assessed in post-mortem brain tissue of AD patients (Winblad et al. 1985;Nazarali and Reynolds 1992;Storga et al. 1996), as well as changes in DA receptor distribution and density in several brain structures of the temporal lobe (Joyce et al. 1993(Joyce et al. , 1998Kemppainen et al. 2003;Kumar and Patel 2007).Transgenic models of AD are widely used to study the role of Ab accumulation and tau tangles in the cognitive alterations characteristi...

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