Functional lateralization of the baso-lateral amygdala neural circuits modulating the motivated exploratory behaviour in rats: role of histamine.

Functional laterality appears to be present in many brain functions in man and animals. The existence of paired neural circuits which act differentially to modulate a specific behavioural function seems to be an evolutionary successful strategy in animal evolution. In spite of many examples described in mammals, birds and other vertebrates and invertebrates, still its intrinsic mechanism is not completely understood. In this work the participation of the baso-lateral amygdala (BLA) on lateralized motivated exploratory behaviour and the possible influence of histamine neurons in these mechanisms were studied in rats. Different groups of animals under xylacine-ketamine anesthesia were implanted with microinjection guide cannulae into the right or left BLA. 72 h after implantation, animals were tested in hole-board cage (OVM) with a novelty object positioned in the center of the arena, as a model of exploration of a non-conflictive environment, and 24h later they were tested in the Elevated Asymmetric Plus Maze (APM) as a model of conflictive exploration. In the day of the experiment, lidocaine was applied into the left, or right BLA in order to block the electrical activity of BLA neurons. Saline in the contralateral BLA was considered control. Results showed that exploratory activity in the OVM was significantly inhibited when lidocaine was microinjected into the left BLA, and no changes were observed when lidocaine was applied into the right BLA. When histamine was microinjected into the right BLA and lidocaine into the contralateral BLA, head-dipping, rearing, and focalized exploration behaviour were significantly inhibited. In the APM, lidocaine treatment increased equally the exploration of the "single wall" and "high and low walls" arms of the labyrinth, independently if blocking of electrical activity of the BLA neurons was performed in the left or right amygdala. Histamine treatment inhibited significantly exploration of the lesser fear-inducing arms of the labyrinth but its effect was more pronounced when histamine microinjection was in the left BLA. In conclusion, present evidence support the lateralized participation of the amygdala on exploratory behaviour and histamine neurons appear to mediate part of these differential modulations.

Cognitive dysfunction and hippocampal changes in experimental type 1 diabetes.

Type 1 diabetes (T1D) is accompanied by a "diabetic encephalopathy" including hypersensitivity to stress, increased risk of stroke, dementia and cognitive impairment. In previous works we reported several brain alterations including a strong decrease in hippocampal proliferation and survival in both spontaneous and streptozotocin-induced models of experimental T1D. The aim of this study was to explore in streptozotocin-treated mice and other parameters associated to mild neurodegeneration in the dentate gyrus and the potential correlation with behavioural changes. The neurogenic status, measured by doublecortin (DCX) expression, showed an important decline in the number of positive cells in the subgranular zone (SGZ). However, neuronal migration was not affected. We found a marked enhancement of intracellular lipofuscin deposits, characteristic of increased oxidative stress and aging in both, the hilus and the SGZ and granular cell layer (GCL). Diabetic mice showed a significant impairment in learning and memory tests, exhibiting a higher latency to show an escape response and a poorer learning efficiency of an active avoiding response compared with control mice. Both, exploratory and non-exploratory activities in a conflictive environment in the asymmetric elevated plus maze were not affected by the diabetic condition. In conclusion, experimental diabetes showed clear signs of changes in the dentate gyrus, changes similar to those present in the aging process. Correlatively, these alterations were in line with a reduced performance in learning and memory tests. The mechanism that could potentially link neural and behavioural disturbances is not yet fully comprehended.

The activation of histamine-sensitive sites of the ventral hippocampus modulates the consolidation of a learned active avoidance response in rats.

Previous evidence from our laboratory has shown that histamine receptors located into the ventral hippocampus modulate learning and memory processes. Stimulation of histamine hippocampal sensitive receptors during the acquisition phase of a conditioned avoidance response to an ultrasonic tone was able to increase latency to escape and impair memory in the rat. Histamine application into the same hippocampal region also impaired the evocation of the response. The purpose of the present work was to evaluate if histaminergic neuron circuits have participation on the consolidation processes of the conditioned avoiding response. Male adult rats were implanted into the ventral hippocampus with microinjection cannulae and subjected consecutively to 2 sessions of 8 trials to learn an avoidance response after an ultrasonic tone of 40 kHz was on, as it was previously described. Immediately after the training period was over, or 15 min after, different groups of rats were microinjected with saline, histamine or a combination of histamine H(1)- or H(2)-receptor antagonists. Twenty four hours later, animals were tested in a new session for the retention of the avoiding response. Results showed that histamine treatment interfered with the consolidation of the avoiding response, affecting latency and the memory efficiency. This interference was mediated by histamine H(1)- and H(2)-receptors, since pretreatment with pyrilamine or ranitidine blocked the inhibitory effect of histamine. Results support the concept that histaminergic neurotransmission modulates learning and memory by affecting selectively the three stages of learning.

Hippocampus and learning. Possible role of histamine receptors

The effect of local adminstration of histamine and its receptor antagonists into the hippocampus on the learning process of an active avoidance response was studied. The task that the animals had to learn consisted in avoiding an electric shock on their feet after a conditioning ultrasonic 40 kHz tone was on. Latency time was defined as the time in serc rats took to avoid or escape the eletric shock: per cent CAR was defined as the cummulative positive responses during learning session. All rats were implanted into the ventral hippocampus with guide cannulae. On the day of the experiment, rats were microinjected through the guide cannulae with 1 mug of saline solution containing 67.5 nmol of ranitidine or pyrilamine alone or in combination with 45 nmol histamine. All groups were subjected to two sessions of learning. Results show that treatment with histamine was effective to block the adquisition of the response, since animals showed a learning curve significantly inferior to that of the controls. Ranitidine treatment was not able to block the histamine effect. Pyrilamine treatment, instead, was effective to block the inhibitory action of histamine on learning. Results suggest that histamine in hippocampus may be exerting a modulatory control on retrieval processes of memory.

Hippocampus and learning. Possible role of histamine receptors

The effect of local adminstration of histamine and its receptor antagonists into the hippocampus on the learning process of an active avoidance response was studied. The task that the animals had to learn consisted in avoiding an electric shock on their feet after a conditioning ultrasonic 40 kHz tone was on. Latency time was defined as the time in serc rats took to avoid or escape the eletric shock: per cent CAR was defined as the cummulative positive responses during learning session. All rats were implanted into the ventral hippocampus with guide cannulae. On the day of the experiment, rats were microinjected through the guide cannulae with 1 mug of saline solution containing 67.5 nmol of ranitidine or pyrilamine alone or in combination with 45 nmol histamine. All groups were subjected to two sessions of learning. Results show that treatment with histamine was effective to block the adquisition of the response, since animals showed a learning curve significantly inferior to that of the controls. Ranitidine treatment was not able to block the histamine effect. Pyrilamine treatment, instead, was effective to block the inhibitory action of histamine on learning. Results suggest that histamine in hippocampus may be exerting a modulatory control on retrieval processes of memory. (AU)