Antonia Gasby

The effect of a high (chocolate) versus low fat/sugar (chow) food on a conditioned-place-preference (CPP) task was evaluated in marmoset monkeys. Anxiety-related behaviors and cortisol levels before and after the CPP task were also measured. Subjects were habituated to a two-compartment CPP box and then, on alternate days, had access to only one compartment during daily 15-min conditionings, for a total of 14 trials. Marmosets were provisioned with chocolate chips in the CC-paired compartment on odd-numbered trials and standard chow in the CW-paired compartment on even-numbered trials. They were then tested for preferring the CC-paired context after a 24-h interval. During the conditioning, a significantly greater amount (in kcal/trial) of chocolate was consumed than chow, yet the foraging pattern of both food types was similar. On the test trial, the time spent in the CC-paired context increased significantly compared to pre-CPP levels, yet this response was not readily predicted b...

Diverse studies indicate that the attention deficit hyperactivity disorder (ADHD) is associated with alterations in encoding processes, including working or short-term memory. Some ADHD dysfunctional domains are reflected in the spontaneously hypertensive rat (SHR). Here SHR-saline group showed significantly poor STM and LTM relative to SD and WKY saline rats. SD and WKY rats treated with d-amphetamine displayed better STM and LTM, compared to SD-vehicle, WKY-vehicle or SHR-d-amphetamine groups.

In this study, the effects on memory of intraperitoneal post-training administration of cyclic nucleotide phosphodiesterase (PDE) inhibitors, DC-TA 46 and rolipram, were tested using a visible/hidden-platform water maze task. The effects of these compounds on cyclic nucleotide levels in the hippocampal formation (HF) and striatum (CP) were also assessed, by enzymatic immunoassay (EIA). The results obtained from rats trained in the visible-platform task were not significantly different from controls. On the contrary, the animals trained in the hidden-platform water maze task showed a memory impairment, when injected with DC-TA 46 at maximal dose of 20mg/kg and with rolipram at 3 and 30 mg/kg doses. The effects of these drugs on cyclic nucleotide levels in HF and CP were observed at 30 min and at 24h after drug administration. Thirty minutes after drug injection, we observed an increase of cAMP level, both in HF and in CP. Twenty-four hours after the retention test, we observed that in CP the cAMP intracellular level remained high, while in the HF at effective doses both inhibitors induced cAMP PDE activity, determining a decrease of cyclic nucleotide. Semi-quantitative RT-PCR analysis, together with Western blot immunodetection, showed a mRNA and protein induction of PDE4D PDE isoforms, that may account for the increase of PDE activity observed. Our data suggest that, despite cyclic nucleotide increase at 30 min, the fundamental event causing memory impairment, came from the subsequent long time decrease of cAMP levels, due to the post-translational PDE4D induction.

ABSTRACT ABSTRACT ABSTRACT Several studies with humans have shown that pictures with emotional content are more easily recognizable than emotionally indifferent pictures. To our knowledge, no attempts have been made to investigate the role of emotional facial expressions to facilitate working memory in non-human primates. In this study we developed a pool of 384 pictures of capuchin monkey (Cebus

In this work, we report the effect of post-training intraperitoneal administration of zaprinast on rat memory retention in the Morris water maze task that revealed a significant memory impairment at the intermediate dose of 10mg/kg. Zaprinast is capable of inhibiting both striatal and hippocampal PDE activity but to a different extent which is probably due to the different PDE isoforms expressed in these areas. To assess the possible involvement of cyclic nucleotides in rat memory impairment, we compared the effects obtained 30min after the zaprinast injection with respect to 24h after injection by measuring both cyclic nucleotide levels and PDE activity. As expected, 30min after the zaprinast administration, we observed an increase of cyclic nucleotides, which returned to a basal level within 24h, with the exception of the hippocampal cGMP which was significantly decreased at the dose of 10mg/kg of zaprinast. This increase in the hippocampal region is the result of a cGMP-specific PDE5 induction, confirmed by sildenafil inhibition, in agreement with literature data that demonstrate transcriptional regulation of PDE5 by cAMP/cGMP intracellular levels. Our results highlight the possible rebound effect of PDE inhibitors.

Physiological hormonal fluctuations during the menstrual cycle, postpartum, and menopause have been implicated in the modulation of mood, cognition, and affective disorders. Taking into account that women's performance in memory tasks can also fluctuate with circulating hormones levels across the menstrual cycle, the cognitive performance in a working memory task for emotional facial expressions, using the six basic emotions as stimuli in the delayed matching-to-sample, was evaluated in young women in different phases of the menstrual cycle. Our findings suggest that high levels of estradiol in the follicular phase could have a negative effect on delayed matching-to-sample working memory task, using stimuli with emotional valence. Moreover, in the follicular phase, compared to the menstrual phase, the percent of errors was significantly higher for the emotional facial expressions of sadness and disgust. The evaluation of the response times (time employed to answer) for each facial expression with emotional valence showed a significant difference between follicular and luteal in reference to the emotional facial expression of sadness. Our results show that high levels of estradiol in the follicular phase could impair the performance of working memory. However, this effect is specific to selective facial expressions suggesting that, across the phases of the menstrual cycle, in which conception risk is high, women could give less importance to the recognition of the emotional facial expressions of sadness and disgust. This study is in agreement with research conducted on non-human primates, showing that fluctuations of ovarian hormones across the menstrual cycle influence a variety of social and cognitive behaviors. Moreover, our data could also represent a useful tool for investigating emotional disturbances linked to menstrual cycle phases and menopause in women.

1. The dopaminergic mesencephalic neurons projecting to the hippocampal formation are distributed in three cell groups: A8 region in the retrorubral field, A9 region in the substantia nigra and A10 region in the ventral tegmental area. 2. Anterograde and retrograde tract-tracing techniques combined with immunohistochemical procedures indicate a topographical organization of mesencephalic dopaminergic projections towards the hippocampal formation. 3. Electrophysiological evidence suggest that dopaminergic mesencephalic neurons could have a regulatory role in suppressing hippocampal excitability. 4. The functional significance of the mesohippocampal dopaminergic system is largely unknown, although it was suggested that this projection could have a role in methamphetamine-produced hypermotility and in modulation of memory processes.

The hippocampal formation has long been thought to play a role in learning and memory. Previous studies from our laboratory examined the organization of mesencephalic projections to the hippocampal formation in the rat. In order to evaluate the effects on learning and memory of retrograde selective lesions of mesencephalic dopaminergic neurons, following bilateral injection of 6-hydroxydopamine in the dorsal and ventral subiculum and adjacent CA1 field of the hippocampal formation, young adult Sprague-Dawley rats were trained in classical inhibitory avoidance, inhibitory avoidance using a multiple trial (training to criterion) and the standard Morris water maze task (cued and spatial versions). With regard to inhibitory avoidance, retention was examined one, three and 10 days after training. Concerning the Morris water maze task, 6-hydroxydopamine-lesioned and sham-operated rats received four training trials on each of four days. After training sessions, the rats were tested during a 60-s probe trial (free-swim trial) in which the platform was removed from the maze. The loss of mesencephalic dopaminergic neurons in the 6-hydroxydopamine-lesioned rats, compared to sham-operated rats, was verified by tyrosine hydroxylase immunohistochemistry. Although the 6-hydroxydopamine-lesioned rats were indistinguishable from sham-operated rats in performing the inhibitory avoidance and the cued version of the Morris water maze task, in the spatial version of the Morris water maze, lesioned rats, compared to controls, exhibited significant differences in the latency (P < 0.05), quadrant time (P < 0.01) and number of platform crossings (P < 0.05). These results suggest that the rat's ability to acquire spatial learning and memory for place navigation in the Morris water maze is likely to be dependent also on the integrity of mesohippocampal dopaminergic connections.

The aim of the present study was to determine, at the light microscopic level, whether the serotonergic fibers originating from the dorsal raphe nucleus (B7), median raphe nucleus (B8) and ventral tegmentum (B9) make putative synaptic contacts with cholinergic neurons of the nucleus basalis magnocellularis and substantia innominata. For this purpose, we utilized: (i) the anterograde transport of Phaseolus vulgaris leucoagglutinin combined with choline acetyltransferase immunohistochemistry; (ii) choline acetyltransferase/tryptophan hydroxylase double immunohistochemistry; and (iii) the FluoroGold retrograde tracer technique combined with tryptophan hydroxylase immunohistochemistry. Following iontophoretic injections of Phaseolus vulgaris leucoagglutinin in the dorsal raphe nucleus, labeling was observed primarily in the ventral aspects of the nucleus basalis magnocellularis and in the intermediate region of the substantia innominata. When Phaseolus vulgaris leucoagglutinin was combined with choline acetyltransferase immunohistochemistry, a close association between the Phaseolus vulgaris leucoagglutinin-positive fibers and cholinergic neurons was observed, even though the majority of the Phaseolus vulgaris leucoagglutinin-immunoreactive terminals seemed to establish contact with non-cholinergic elements. Following Phaseolus vulgaris leucoagglutinin injection in the median raphe nucleus, very few labeled fibers with no evident close contact with nucleus basalis magnocellularis and substantia innominata cholinergic neurons were observed. After tryptophan hydroxylase/choline acetyltransferase double immunohistochemistry, a plexus of serotonergic (tryptophan hydroxylase-positive) fibers in the vicinity of choline acetyltransferase-immunoreactive neurons of the substantia innominata and nucleus basalis magnocellularis was observed, and some serotonergic terminals have been shown to come into very close contact with the cholinergic cells. Most of the tryptophan hydroxylase-immunoreactive terminals seem to establish contacts with non-cholinergic cells. Following FluoroGold injection in the nucleus basalis magnocellularis and substantia innominata, the majority of retrogradely labeled neurons was observed mainly in the ventromedial cell group of the dorsal raphe nucleus. In this area, a minority of the FluoroGold-positive neurons was tryptophan hydroxylase immunoreactive. These findings show that serotonergic terminals, identified in very close association with the cholinergic neurons in the substantia innominata and nucleus basalis magnocellularis, derive primarily from the B7 serotonergic cell group of the dorsal raphe nucleus, and provide the neuroanatomical evidence for a direct functional interaction between these two neurotransmitter systems in the basal forebrain.

Emerging evidence supports the role of the cerebellum in motor learning and previous studies have also shown that olivary projections to the cerebellum are involved in motor learning. Since the pontine nuclei make up the other main relay centre in the cerebro-cerebellar pathway, the purpose of the present study was to verify the involvement of the ponto-cerebellar pathway in motor and spatial learning, by comparing these functions in intact animals and in rats with selective injury of the olivary or pontine neurons. Two groups of rats were used: the first was treated with 3-acetylpyridine to destroy the inferior olivary complex, the second received electrolytic lesions of the middle cerebellar peduncle to interrupt the ponto-cerebellar pathway. Control and lesioned rats were then submitted to three tasks: unrotated rod, rota-rod at 20 r.p.m., and Morris water maze. In the first task both 3-acetylpyridine-treated rats and rats with lesions of the middle cerebellar peduncle showed static equilibrium deficiencies. Through training, however, they reached the maximal score attained by the controls. The rats submitted to the rota-rod at 20 r.p.m. obtained scores significantly inferior to the controls. The Morris water maze results indicated that the lesion of inferior olivary complex and middle cerebellar peduncle both alter learning of the spatial task. These findings show that both the ponto- and olivo-cerebellar pathways are involved in learning complex motor sequences and spatial tasks. Since both projections converge onto Purkinje cells, our results suggest an integration of these two pathways in the cerebellar control of learning mechanism.

The dopaminergic neurons in the midbrain of the rat are located in three groups: the ventral tegmental area (VTA-A10), substantia nigra (SN-A9), and retrorubral field (RRF-A8). We have recently examined the organization of the projections from the VTA and the SN to the hippocampal formation (HF) in the rat. In the present study we characterize the projections of the RRF to the HF by using anterograde tracing, retrograde tracers, and tyrosine hydroxylase (TH) immunohistochemistry. Following iontophoretical injections of Phaseolous vulgaris leucoagglutinin (PHA-L) into the RRF, anterograde labeling was observed primarily in the ipsilateral subiculum and adjacent CA1 cell field. Sparse labeling was also observed in the CA3 cell field and dentate gyrus. The distribution of RRF neurons projecting to the HF was examined by injecting retrograde fluorescent tracers (fluorogold, fast blue, and nuclear yellow) into several hippocampal areas. The retrograde tracer findings indicate that the medial aspects of the RRF project to the subiculum and adjacent CA1 cell field of both the septal and temporal HF. In order to evaluate the percentage of dopaminergic cells of the RRF projecting to the HF, the retrograde neuronal tracer fluorogold was used in combination with TH immunohistochemistry. The quantitative evaluation of retrograde labeled and TH-immunoreactive (IR) cells showed that RRF projections to the HF are partially (10-18%) dopaminergic. The findings suggest that the general pattern of distribution and organization of the RRF-A8 projections to the HF is similar to that observed in our previous studies examining hippocampal afferents from the VTA and SN. The data also suggest a crude topographical organization of RRF afferents to the HF and a more prominent input to the temporal than to the septal HF.

These experiments examined the interaction between muscarinic cholinergic and dopaminergic systems in the modulation of memory storage. Male CD1 mice (25-30 g) were trained in an inhibitory avoidance (IA) and a Y-maze discrimination (YMD) task. The first experiment examined the dose-response effects, on retention, of agonists and antagonists specific for either D1- or D2-receptors. Immediately posttraining mice were given i.p. injections of saline, the D1-receptor agonists SKF 38393 (3.0, 10.0 or 30.0 mg/kg) or SKF 77434 (3.0, 10.0 or 30.0 mg/kg), the D1-receptor antagonist SCH 23390 (0.03, 0.1, or 1.0 mg/kg), the D2-receptor agonist quinpirole (0.3, 1.0 or 3.0 mg/kg) or the D2-receptor antagonist sulpiride (3.0, 10.0, 30.0 or 100.0 mg/kg). Retention was tested 48 h later. The drugs affecting D1-receptors did not affect retention. In contrast, in both tasks quinpirole enhanced retention and sulpiride impaired retention. In the IA task, quinpirole (3.0 mg/kg) blocked the retention impairing effects of the muscarinic cholinergic antagonist atropine (10.0 mg/kg), and sulpiride (3.0, 10.0, 30.0 or 100.0 mg/kg) significantly attenuated the memory enhancing effects of the muscarinic cholinergic agonist oxotremorine (35.0 or 70.0 micrograms/kg). D1-receptor agents did not modify the effects of either atropine or oxotremorine on retention of the IA response. These findings suggest that the effects of cholinergic muscarinic agents on retention of the IA response are mediated by influences involving D2-dopaminergic mechanisms. In the YMD task, atropine (10.0 mg/kg) blocked the memory-enhancing effects of quinpirole (3.0 mg/kg) and oxotremorine (35.0 or 70.0 micrograms/kg) attenuated the memory impairing effect of sulpiride (3.0, 10.0, 30.0 or 100.0 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Recent studies suggest that both sex and cerebral hemisphere influence brain mechanisms associated with emotional memory. Here we used evoked potentials to examine the influence of sex and hemisphere on brain responses to emotional stimuli. Given that the P300 component of the event-related brain potential (ERP) is considered a cognitive neuroelectric phenomenon, we compared left and right hemisphere P300 responses to brief (2 s) presentations of emotionally arousing pictures in men and women. P300 waves were recorded from sites overlying left (F3 and P3) and right (F4 and P4) hemisphere frontal and parietal locations in response to a series of standardized pictures rated as emotionally negative, positive, or neutral. Negative pictures elicited more robust P300 effects, as indexed by both amplitude and latency measures, in the left hemisphere in women than in men, yet elicited a stronger P300 component in the right hemisphere in men than in women. The variables of sex and hemisphere interacted significantly to influence the strength of the P300 component to the negative slides. Negative slides were also best recalled at a long-term, incidental memory test, a fact potentially related to the differential P300 waves at encoding. These data further support the view that both sex and cerebral hemisphere represent relevant, interacting influences on neural correlates of emotion, and of emotionally influenced memory.

These experiments examined the interaction of muscarinic and dopaminergic systems in influencing memory for one-trial inhibitory avoidance training in mice of the C57BL/6 and DBA/2 strains. In both strains, immediate post-training systemic administration of the muscarinic cholinergic agonist oxotremorine enhanced retention and the cholinergic antagonist atropine impaired retention. No effects were seen with injections 2 h post-training. Furthermore, the drugs did not affect retention performance of animals that received no footshock on the training trial. These results confirm previous findings indicating that muscarinic cholinergic drugs affect memory by influencing memory consolidation. In C57 mice, pretreatment with selective D1 or D2 dopamine (DA) receptor agonists (SKF 38393 or LY 171555, respectively) in otherwise non-effective doses (5 and 0.25 mg/kg, respectively) potentiated the effects of oxotremorine (0.04 mg/kg). Furthermore, in C57 mice pretreatment with selective D1 or D2 receptor antagonists (SCH 23390 or (-)-sulpiride) in otherwise non-effective doses (0.025 and 6 mg/kg, respectively) blocked the memory enhancing effects of oxotremorine. The memory impairing effects of atropine (3 mg/kg) were blocked by the D1 and D2 selective agonists and potentiated by the selective D1 or D2 antagonists. In contrast, in DBA mice, the D1 and D2 selective agonists antagonised the memory enhancing effects of oxotremorine (0.02 mg/kg) and potentiated the effects of atropine (2 mg/kg). Furthermore, the D1 and D2 antagonists potentiated the effects of oxotremorine and antagonised those of atropine. These findings indicate that although muscarinic cholinergic influences on memory storage are comparable in mice of these two strains, the cholinergic-dopaminergic interactions are opposite in the two strains. These results have implications for hypotheses of cholinergic and dopaminergic regulation of memory storage.

The abundance of serotonin (5-HT) in the central nervous system can explain its role in the regulation of various functions, such as sleep, feeding, sexuality, emotional status, and pain. In addition, 5-HT localized in "cognitive pathways" with hippocampus and frontal cortex as the main target structures, is involved in learning and memory processes. Recent studies led to the discovery of various types and subtypes of receptors, differentially associated to cognitive mechanisms. Abundant data available reveals that the administration of 5-HT(2A/2C) and 5-H(T4) receptor agonists, or 5-HT(1A), 5-HT(3) and 5-HT(1B) antagonists improves memory and has a facilitatory effect on learning in situations involving a high cognitive demand. On the contrary 5-HT(2A/2C) and 5-HT(4) receptors antagonists, or 5-HT(1A), 5-HT(3) and 5-HT(1B) receptors agonists have opposite effects. Although these results are contradictory, or even opposite, it is important to take into account the effect of global, and unspecific, stimulation of serotonergic receptors and the activation of other neurotransmission systems, together with the type of task used, the way it is administered and the ligand affinity. The aim of this review is to clarify the behavioral role of the recently discovered 5-HT(7)-type receptor and highlight its involvement in the modulation of learning and memory processes, thus providing a basis to obtain new therapeutic agents and strategies for the treatment of learning and memory disorders.

Several studies suggest that emotional arousal can promote memory storage. In this study, we evaluated the effects of emotional content on declarative memory, utilizing an adaptation of two versions of the same story, with different arousing properties (neutral or emotional), which have been already employed in experiments involving the enhancing effects of emotions on memory retention. We used event related potentials (ERP) to evaluate whether there is a sex-related hemispheric lateralization of electrical potentials elicited by the emotional content of a story. We compared left and right hemisphere P300 waves, recorded in P3 and P4 electrode sites, in response to emotional or neutral stimuli in men and women. In the left hemisphere, emotional stimuli elicited a stronger P300 in women, compared to men, as indexed by both amplitude and latency measures; moreover, the emotional content of the story elicited a stronger P300 in the right hemisphere in men than in women. The better memory for the arousal material may be related to the differential P300 at encoding. These data indicate that both sex and cerebral hemisphere constitute important, interacting influences on neural correlates of emotion, and of emotionally influenced memory.