José L. Valdés

Arousal and differential Fos expression in histaminergic neurons of the ascending arousal system during a feeding-related motivated behaviour

Arousal depends on the concerted activity of the ascending arousal system (AAS) but specific stimuli may primarily activate some nuclei of this system. Motivated behaviours are characterized by behavioural arousal, although it is not known which AAS nuclei are active during a motivated behaviour. To address this issue, rats were rendered motivated for food by fasting them for 1 day and then were enticed with food that they could not obtain for varying periods of time. We studied the level of arousal by polysomnography or radiotelemetry, and Fos‐ir in the AAS, during food enticing. We found a strong arousal and an early increase in Fos‐ir in the histaminergic neurons from the tuberomammillary nucleus, after 30 min of enticing, followed by increased Fos‐ir in the whole AAS if food enticing was prolonged to 1 or 2 hours. In contrast, food presentation to non‐motivated rats did not increase arousal or Fos‐ir in the tuberomammillary nucleus. As opposed to the active arousal of the motivated rats, passive arousal induced by sensory stimulation was associated with increased Fos‐ir in the locus coeruleus and the orexin neurons, but not with increased Fos‐ir in the tuberomammillary nucleus or in the other nuclei of the AAS. We conclude that the arousal during feeding‐related motivated behaviour is associated primarily with the activation of the tuberomammillary nucleus, while the other arousal‐related nuclei become active later on.

Regulation of Memory Formation by the Transcription Factor XBP1

Contextual memory formation relies on the induction of new genes in the hippocampus. A polymorphism in the promoter of the transcription factor XBP1 was identified as a risk factor for Alzheimers disease and bipolar disorders. XBP1 is a major regulator of the unfolded protein response (UPR), mediating adaptation to endoplasmic reticulum (ER) stress. Using a phenotypic screen, we uncovered an unexpected function of XBP1 in cognition and behavior. Mice lacking XBP1 in the nervous system showed specific impairment of contextual memory formation and long-term potentiation (LTP), whereas neuronal XBP1s overexpression improved performance in memory tasks. Gene expression analysis revealed that XBP1 regulates a group of memory-related genes, highlighting brain-derived neurotrophic factor (BDNF), a key component in memory consolidation. Overexpression of BDNF in the hippocampus reversed the XBP1-deficient phenotype. Our study revealed an unanticipated function of XBP1 in cognitive processes that is apparently unrelated to its role in ER stress.

The histaminergic tuberomammillary nucleus is critical for motivated arousal

Obtaining food, shelter or water, or finding a mating partner are examples of motivated behaviors, which are essential to preserve the species. The full expression of such behaviors requires a high but optimal arousal state. We tested the idea that tuberomammillary nucleus (TMN) histamine neurons are crucial to generate such motivated arousal, using a model of the appetitive phase of feeding behavior. Hungry rats enticed with food within a wire mesh box showed intense goal‐directed motor activity aimed at opening the box, an increase in core temperature, a fast histamine release in the hypothalamus and an early increase in Fos immunoreactivity in TMN and cortical neurons. Enticing with stronger‐tasting food induced stronger motor, temperature and Fos immunoreactivity brain responses than ordinary food pellets. TMN lesion greatly decreased all of those responses. We conclude that histamine neurons increase arousal and vegetative activity, allowing the normal unfolding of voluntary, goal‐directed behavior such as obtaining food.

Specific activation of histaminergic neurons during daily feeding anticipatory behavior in rats.

When food is available during a restricted and predictable time of the day, animals show increased locomotor and food searching behaviors before the anticipated daily meal. We had shown that histamine-containing neurons are the only aminergic neurons related to arousal that become active in anticipation of an upcoming meal. To further map, the brain regions involved in the expression of the feeding-anticipatory behavior, we quantified the expression of Fos in hypothalamic areas involved in arousal. We found that nearly 35% of the histamine neurons from the tuberomammillary nucleus were Fos-immunoreactive immediately before mealtime. One hour before this transient increase in Fos-immunoreactivity, we found a similarly brief increase of fos mRNA in the tuberomammillary nucleus. In contrast, the activation of two types of perifornical hypothalamic neurons followed meal onset by 1-2 h. One neuron type was orexin/hypocretin-immunoreactive, while the other type was neither orexin nor melanin concentrating hormone-immunoreactive. The present work indicates that the increased locomotor activity that anticipates mealtime coincides with the activation of the tuberomammillary nucleus, and that the behavioral activation during the consummatory phase of feeding coincides more closely with the delayed activation of the perifornical hypothalamic area.

Differential effects of infralimbic cortical lesions on temperature and locomotor activity responses to feeding in rats

The time of food availability induces important behavioral and metabolic adaptations. Animals subjected to feeding restricted to a few daytime hours show increased locomotor activity and body temperature in anticipation of mealtime. In addition, animals under ad libitum feeding show a marked postprandial raise in body temperature and in thermogenesis. The areas of the brain commanding these responses to food are partially known. We investigated in the rat the role of the infralimbic area, located in the medial prefrontal cortex, and considered a visceral-autonomic motor area, in the responses to ad libitum or restricted feeding schedule. We performed infralimbic cortex excitotoxic lesions using injections of ibotenic acid, and measured body temperature and locomotor activity by telemetry in rats under ad libitum and restricted feeding conditions. We found that bilateral infralimbic area lesions prevented both the anticipatory and the postprandial increases in core temperature, decreased mean temperature by nearly 0.3 degrees C during both light/dark phases, and increased daily temperature variability. In contrast, the lesion caused a rapid induction of the anticipatory locomotor activity. These results show that behavioral and metabolic responses to the time of food availability are commanded separately and that the infralimbic area is a key structure to adjust the body temperature to an upcoming meal.

Histamine and motivation

Brain histamine may affect a variety of different behavioral and physiological functions; however, its role in promoting wakefulness has overshadowed its other important functions. Here, we review evidence indicating that brain histamine plays a central role in motivation and emphasize its differential involvement in the appetitive and consummatory phases of motivated behaviors. We discuss the inputs that control histaminergic neurons of the tuberomamillary nucleus (TMN) of the hypothalamus, which determine the distinct role of these neurons in appetitive behavior, sleep/wake cycles, and food anticipatory responses. Moreover, we review evidence supporting the dysfunction of histaminergic neurons and the cortical input of histamine in regulating specific forms of decreased motivation (apathy). In addition, we discuss the relationship between the histamine system and drug addiction in the context of motivation.

The parietal association cortex of the rat.

Spatial cognition is a complex higher function in mammals and is involved in a variety of tasks that can be explored in the laboratory. In this review we will discuss the role of the posterior parietal/anteromedial cortex of rodents, also known as the parietal association cortex, and the hippocampal formation in spatial navigation. We will also discuss other higher associational functions of the posterior parietal/anteromedial cortex as they relate to Dr. Pinto-Hamuys contribution to understanding behavioral functions.

Offline reactivation of experience-dependent neuronal firing patterns in the rat ventral tegmental area

In a rest period immediately after a task, neurons in the hippocampus, neocortex, and striatum exhibit spatiotemporal correlation patterns resembling those observed during the task. This reactivation has been proposed as a neurophysiological substrate for memory consolidation. We provide new evidence that rodent ventral tegmental area (VTA) neurons are selective for different types of food stimuli and that stimulus-sensitive neurons strongly reactivate during the rest period following a task that involved those stimuli. Reactivation occurred primarily during slow wave sleep and during quiet awakeness. In these experiments, VTA reactivation patterns were uncompressed and occurred at the firing rate level, rather than on a spike-to-spike basis. Mildly aversive stimuli were reactivated more often than positive ones. The VTA is a pivotal structure involved in the perception and prediction of reward and stimulus salience and is a key neuromodulatory system involved in synaptic plasticity. These results suggest new ways in which dopaminergic signals could contribute to the biophysical mechanisms of selective, system-wide, memory consolidation, and reconsolidation during sleep.

The Histaminergic Tuberomamillary Nucleus Is Involved in Appetite for Sex, Water and Amphetamine

The histaminergic system is one component of the ascending arousal system which is involved in wakefulness, neuroendocrine control, cognition, psychiatric disorders and motivation. During the appetitive phase of motivated behaviors the arousal state rises to an optimal level, thus giving proper intensity to the behavior. Previous studies have demonstrated that the histaminergic neurons show an earlier activation during the appetitive phase of feeding, compared to other ascending arousal system nuclei, paralleled with a high increase in arousal state. Lesions restricted to the histaminergic neurons in rats reduced their motivation to get food even after 24h of food deprivation, compared with intact or sham lesioned rats. Taken together, these findings indicate that the histaminergic system is important for appetitive behavior related to feeding. However, its role in other goal-directed behaviors remains unexplored. In the present work, male rats rendered motivated to obtain water, sex, or amphetamine showed an increase in Fos-ir of histaminergic neurons in appetitive behaviors directed to get those reinforcers. However, during appetitive tests to obtain sex, or drug in amphetamine-conditioned rats, Fos expression increased in most other ascending arousal system nuclei, including the orexin neurons in the lateral hypothalamus, dorsal raphe, locus coeruleus and laterodorsal tegmental neurons, but not in the ventral tegmental area, which showed no Fos-ir increase in any of the 3 conditions. Importantly, all these appetitive behaviors were drastically reduced after histaminergic cell-specific lesion, suggesting a critical contribution of histamine on the intensity component of several appetitive behaviors.

Lack of phonotactic preferences of female frogs and its consequences for signal evolution

Sexual selection is one of the main evolutionary forces that drive signal evolution. In previous studies, we have found out that males of Pleurodema thaul, a frog with an extensive latitudinal distribution in Chile, emits advertisement calls that show remarkable variation among populations. In addition, this variation is related to intense inter-male acoustic competition (intra-sexual selection) occurring within each population. However, the extent to which female preferences contribute to the signal divergence observed is unclear. To study the responsiveness of females in each population, we stimulated females with synthetic calls designed with the acoustic structure of their own population and subsequently responsive females were subjected to a two-choice experiment, where they were stimulated with synthetic calls of their own population versus a call of a foreign population. Females do not show phonotactic preferences for calls of their own or foreign populations as measured with both linear and circular variables. The lack of phonotactic preferences suggests an absence of participation of inter-sexual selection processes in the divergence of the acoustic signals of P. thaul, highlighting the importance of intra-sexual selection for the evolution of these signals. These results concur with studies in other vertebrates emphasizing the relevance of interactions among males for the evolution of acoustic communication systems.