Tellurium epigenetic transgenerational effects on behavioral expression of coping behavior in rats.

An increasing interest has been developed in the past 15 years in the relationship between trace elements and cell functioning. In the present work the possibility of transgenerational effects of Te was investigated in rats. F1 generation exposed to K2TeO3 (1.55nM) from day 1 of pregnancy until litters were 30 day old, these animals with no other treatment than tap water and food were let to reach 60-70 day old. At this age, female rats were mated with normal untreated male rats. The F2 generation also without any Te treatment was allowed to grow until 30 days of age. At this age, behavioral tests measuring exploration induced by novelty, lateralized exploration, social interaction and survival behavior were applied. Results showed that head-dipping, rearing, lateralized exploration, social interaction, and survival behaviors, affected by Te treatment in F1 generation, also were modified in the same manner in F2 generation. These data show that Te effects on coping behavior in rats are preserved epigenetically in the next generation.

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.

The role of histamine on cognition.

Histamine was intensively studied at the beginning of the 20th century because of its important role in allergic and inflammation processes. In those days it was very difficult that researchers could envisage another impacting function for the imidazolamine in the living systems. Once the imidazolamine was found located in neuron compartment in the brain, increasing evidence supported many regulatory functions including its possible role in memory and learning. The specific participation of histamine in cognitive functions followed a slow and unclear pathway because the many different experimental learning models, pharmacologic approaches, systemic and localized applications of the histamine active compounds into the brain used by researchers showed facilitating or inhibitory effects on learning, generating an active issue that has extended up to present time. In this review, all these aspects are analyzed and discussed considering the many intracellular different mechanisms discovered for histamine, the specific histamine receptors and the compartmentalizing proprieties of the brain that might explain the apparent inconsistent effects of the imidazolamine in learning. In addition, a hypothetical physiologic role for histamine in memory is proposed under the standard theories of learning in experimental animals and humans.

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.

Motivated exploratory behaviour in the rat: the role of hippocampus and the histaminergic neurotransmission.

Exploration is one of most basic adaptive behavioural responses, giving the animal an important evolutionary advantage to survive in a changing environment. Inspection of novel environments might be come with motivated exploratory behaviour. In spite that this type of exploration in the rat is known for many years, little attention has been given to the intrinsic mechanisms or the brain structures that are involved in. In the present work the hippocampus, the neurotransmitter histamine, and the geometrical features of novel objects were examined in a model of conflictive and non-conflictive exploration in the rat which evaluates incentive-motivated exploration. Young adult intact rats were tested in a neutral non-conflictive behavioural activity detector (OVM), with (eOVM) or without (sOVM) novel objects. Three different objects were used: a box, a toy duck, and a tower. Results show that animals decrease its general motor activity (horizontal, ambulatory and non-ambulatory activity) in favor to exploration of the objects. Motivated exploration was not the same for all three objects. Rats explored significantly more the Tower and the Box objects than the Duck item. Behavioral patterns of hippocampus-implanted rats showed decreased scores in motor activity but maintained the difference in the relation of "without/with objects" exploration. When hippocampus-implanted rats were tested in a conflictive exploration device (the elevated asymmetric plus-maze), exploration of the No Wall arm, considered the most fear-inducing environment, was significantly more explored by the animal when the tower object was positioned at its end than when it was absent. Microinjection into the ventral hippocampus of histamine abolished this motivated exploratory response. Pre-treatment with pyrilamine, and not with ranitidine, was effective to block the inhibitory effect of histamine on the object motivated exploration. Results confirm that the hippocampus is involved on incentive motivated exploration, and suggest that histamine is part of an analyzing neuronal circuit of novelty incentivating behavioural responses in rats.

Glutamic acid and histamine-sensitive neurons in the ventral hippocampus and the basolateral amygdala of the rat: functional interaction on memory and learning processes.

The possibility of a functional interaction between the amygdala and the ventral hippocampus during learning of a conditioned avoidance response when both brain structures are chemically stimulated with glutamic acid and/or histamine receptor antagonists (pyrilamine, H1-histamine antagonist and ranitidine, H2-histamine receptor antagonist) was studied in rats. Adult male rats were stereotaxically implanted with guide cannulae into the basolateral amygdala (A) and the ventral hippocampus (H). Seventy-two hours after the implant, rats were microinjected with 1 microl of saline solution, 10 nmol glutamic acid or 45 nmol of histamine receptor antagonists in several brain structures combinations. These combinations were: HsalAsal; HmsgAmsg; HmsgAsal; HsalAmsg; HpyrAmsg; HmsgApyr; HranAmsg and HmsgAran. Five minutes after the injection, rats were subjected to a learning task which consisted to avoid an electric shock applied to the animal's feet when an ultrasonic tone of 40 kHz is on for 30 s. Results showed that the simultaneous application of glutamic acid into hippocampus and amygdala interfered with the latency to escape and memory consolidation process. Stimulation with glutamic acid alone into the hippocampus or into the amygdala (HsalAmsg and HmsgAsal groups) interfered slightly with latency but impaired the consolidation process. Blocking the H1-histamine receptors of the amygdala affected slightly latency and efficiency of learning, meanwhile the blocking of H2-histamine receptors interfered with both parameters. Blocking H1- and H2-histamine receptors of the hippocampus significantly impaired latency and efficiency of learning of rats stimulated with glutamic acid into the amygdala. In conclusion, the experimental evidence suggests that hippocampal glutamic acid-neurons functionally interact with histamine-neurons in the basolateral amygdala to modulate memory and learning process.

Chronic aerial exposure to glucorticoids or beta-agonists affects avoidance learning and exploratory motivation in rats.

The purpose of the present work was to examine if the conventional asthma treatments in humans (inhalation of glucocorticoids or beta-agonists, administered in a chronic regimen) might affect behavioral processes (learning and exploratory motivation) in rats. Adult male rats were exposed to an atmosphere saturated with either saline, budesonide (a glucocorticoid), or salbutamol (a beta-adrenergic receptor agonist) in a forced ventilation cage, connected to a nebulizer for 5 min twice a day for 15 days at the same hours of the day. Doses of budesonide in the nebulizing solution were 0.116, 1.16, and 11.6mM. Doses of salbutamol in the nebulizing solution were 1.3, 13, and 130 mM. Forty-eight hours after treatment, the different groups were subjected to exploration of an elevated asymmetric plus-maze (APM, model of exploratory motivation), and 24h later to learning of an avoidance response to an ultrasonic tone in a two-compartment cage (model of memory and learning). Results showed that budesonide induces moderate effects on exploratory motivation. In one of the fear-inducing arms (single wall arm), exploration decreased and this effect was not dose dependent. In the cognitive model, glucocorticoids affected slightly the latency to escape but with no interference in memory efficiency. On the other hand, at the lower dose in the APM, salbutamol increased significantly the exploration of both fear-inducing arms (no walls and single wall arms). In the learning model, the beta-agonist induced two opposing effects. The lower dose (1.3mM) facilitated learning and the higher dose (13 mM) inhibited learning instead. In conclusion, results are compatible with the notion that inhaled glucocorticoids or beta-agonists might cross the lung aerial barrier into the blood compartment, exerting effects on learning and motivation functions.

Histaminergic neurons of the ventral hippocampus and the baso-lateral amygdala of the rat: functional interaction on memory and learning mechanisms.

The possibility of a functional interaction between the amygdala and the ventral hippocampus on learning of a conditioned avoidance response when both brain structures are chemically stimulated with histamine was studied in rats. Adult male rats were stereotaxically implanted under ether anaesthesia with guide cannulae into the baso-lateral amygdala and the ventral hippocampus. Seventy-two hours after the implant, rats were microinjected with: 1 microl saline solution into both structures (SAL+SAL group); 9 or 90 nmol doses of histamine into both structures (HA+HA groups); 9 or 90 nmol histamine into the hippocampus and saline into the amygdala (HA+SAL groups); saline into the hippocampus and 9 or 90 nmol histamine into the amygdala (SAL+HA groups). Five minutes following the injection, rats were subjected to a learning task in eight consecutive trials, consisting of avoiding an electric shock applied to the feet of the animal when an ultrasonic tone of 40 kHz is on for 30 s. Results show that histamine applied in any dose into both amygdala and hippocampus was able to significantly increase the escape latency and impair the efficacy of learning. Chemical stimulation with histamine of only hippocampus or amygdala affected selectively the escape latency. Results suggest that there is a functional interaction between histamine-sensitive neurons of the amygdala and hippocampus during processing of a learning task.

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)