Effects of Acute Stress or Centrally Injected Interleukin-1beta on Neuropeptide Expression in the Immune System

Acute stress stimulates the expression and release of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from the hypothalamus, and the pro-opiomelanocortin products beta-endorphin and ACTH from the anterior pituitary. These neuropeptides are also expressed in immune tissues, and it has been proposed that they may modulate immune responses to stress through paracrine mechanisms. We subjected rats to restraint stress or central injection of interleukin (IL)-1beta to determine whether these acute stimuli can alter the expression of neuropeptides in the spleen and thymus. Restraint stress significantly increased the contents of all these neuropeptides in thymic, but not splenic, extracts. A single icv injection of IL-1beta increased contents of CRH, AVP, ACTH and beta-endorphin in the spleens of both sham-operated and adrenalectomised (ADX) rats. IL-1beta increased thymic contents of CRH and ACTH in sham-operated rats but these increases were not observed in ADX rats. These results suggest that the effects of IL-1beta on neuropeptide expression in the spleen are independent of glucocorticoids, whereas IL-1beta stimulation of neuropeptide expression in the thymus is dependent on circulating glucocorticoids. There were significant correlations between increases in CRH, ACTH and beta-endorphin in the spleen, and between CRH and ACTH in the thymus, consistent with the suggestion that IL-1beta-induced increases in ACTH and beta-endorphin may be mediated through CRH. These results provide evidence that stressors can directly influence neuropeptide expression in immune tissues. Thus stress may influence immune functions through paracrine mechanisms involving locally synthesised neuropeptides as well as through activation of the hypothalamo-pituitary-adrenal axis.     

Towards mouse models of perseveration: a heritable component in extinction of operant behavior in fourteen standard and recombinant inbred mouse lines

Extinction of instrumental responses is an essential skill for adaptive behavior such as foraging. So far, only few studies have focused on extinction following appetitive conditioning in mice. We studied extinction of appetitive operant lever-press behavior in six standard inbred mouse strains (A/J, C3H/HeJ, C57BL/6J, DBA/2J, BALB/cByJ and NOD/Ltj) and eight recombinant inbred mouse lines. From the response rates at the end of operant and extinction training we computed an extinction index, with higher values indicating better capability to omit behavioral responding in absence of reward. This index varied highly across the mouse lines tested, and the variability was partially due to a significant heritable component of 12.6%.To further characterize the relationship between operant learning and extinction, we calculated the slope of the time course of extinction across sessions. While many strains showed a considerable capacity to omit responding when lever pressing was no longer rewarded, we found a few lines showing an abnormally high perseveration in lever press behavior, showing no decay in response scores over extinction sessions.No correlation was found between operant and extinction response scores, suggesting that appetitive operant learning and extinction learning are dissociable, a finding in line with previous studies indicating that these forms of learning are dependent on different brain areas. These data shed light on the heritable basis of extinction learning and may help develop animal models of addictive habits and other perseverative disorders, such as compulsive food seeking and eating.     

ENSEMBLE RECORDINGS IN AWAKE RATS: ACHIEVING BEHAVIORAL REGULARITY DURING MULTIMODAL STIMULUS PROCESSING AND DISCRIMINATIVE LEARNING

To meet an increasing need to examine the neurophysiological underpinnings of behavior in rats, we developed a behavioral system for studying sensory processing, attention and discrimination learning in rats while recording firing patterns of neurons in one or more brain areas of interest. Because neuronal activity is sensitive to variations in behavior which may confound the identification of neural correlates, a specific aim of the study was to allow rats to sample sensory stimuli under conditions of strong behavioral regularity. Our behavioral system allows multimodal stimulus presentation and is coupled to modules for delivering reinforcement, simultaneous monitoring of behavior and recording of ensembles of well isolated single neurons. Using training protocols for simple and compound discrimination, we validated the behavioral system with a group of 4 rats. Within these tasks, a majority of medial prefrontal neurons showed significant firing‐rate changes correlated to one or more trial events that could not be explained from significant variation in head position. Thus, ensemble recordings can be combined with discriminative learning tasks under conditions of strong behavioral regularity.     

Hypothalamo-Pituitary-Adrenocortical Regulation Following Lesions of the Central Nucleus of the Amygdala

Previous reports indicate that the central nucleus of the amygdala (CeA) stimulates adrenocorticotropin and corticosterone secretion, suggesting a role for this region in central hypothalamo-pituitary-adrenocortical (HPA) stress regulation. To evaluate this hypothesis, this study assessed the impact of CeA lesion on the response of hypophysiotrophic paraventricular nucleus (PVN) neurons to acute restraint and chronic unpredictable stress exposure. In contrast to previous reports, CeA lesions did not affect corticosterone or ACTH secretion induced by acute stress. Acute restraint increased PVN corticotropin releasing hormone (CRH) mRNA expression, increased the number of parvocellular PVN neurons expressing the co-secretagogue arginine vasopressin (AVP), and induced cFOS mRNA expression in the parvocellular PVN. However, there was no additional effect of CeA lesion on any measure of PVN activation. Chronic unpredictable stress exposure induced long-term activation of the HPA axis, noted by thymic involution, adrenal hypertrophy and increased PVN CRH mRNA expression. Stress-induced changes in thymus and adrenal weights were not affected by CeA lesion. Further, CeA lesion rats did not differ from controls in post-stress CRH mRNA expression. However, basal CRH mRNA expression was increased in the PVN of CeA rats, suggesting that the CeA plays a role in long-term inhibition of the PVN. The results of these studies are not consistent with the hypothesis that the CeA is necessary for stress-induced pituitary-adrenocortical activation. Rather, this region may play a stressor-specific modulatory role in regulation of HPA function.     

The hippocampus: hub of brain network communication for memory

A complex brain network, centered on the hippocampus, supports episodic memories throughout their lifetimes. Classically, upon memory encoding during active behavior, hippocampal activity is dominated by theta oscillations (6-10Hz). During inactivity, hippocampal neurons burst synchronously, constituting sharp waves, which can propagate to other structures, theoretically supporting memory consolidation. This 'two-stage' model has been updated by new data from high-density electrophysiological recordings in animals that shed light on how information is encoded and exchanged between hippocampus, neocortex and subcortical structures such as the striatum. Cell assemblies (tightly related groups of cells) discharge together and synchronize across brain structures orchestrated by theta, sharp waves and slow oscillations, to encode information. This evolving dynamical schema is key to extending our understanding of memory processes.     

Neural coding of reward magnitude in the orbitofrontal cortex of the rat during a five-odor olfactory discrimination task

The orbitofrontal cortex (OBFc) has been suggested to code the motivational value of environmental stimuli and to use this information for the flexible guidance of goal-directed behavior. To examine whether information regarding reward prediction is quantitatively represented in the rat OBFc, neural activity was recorded during an olfactory discrimination “go”/“no-go” task in which five different odor stimuli were predictive for various amounts of reward or an aversive reinforcer. Neural correlates related to both actual and expected reward magnitude were observed. Responses related to reward expectation occurred during the execution of the behavioral response toward the reward site and within a waiting period prior to reinforcement delivery. About one-half of these neurons demonstrated differential firing toward the different reward sizes. These data provide new and strong evidence that reward expectancy, regardless of reward magnitude, is coded by neurons of the rat OBFc, and are indicative for representation of quantitative information concerning expected reward. Moreover, neural correlates of reward expectancy appear to be distributed across both motor and nonmotor phases of the task.     

Identification and integration of sensory modalities: Neural basis and relation to consciousness

A key question in studying consciousness is how neural operations in the brain can identify streams of sensory input as belonging to distinct modalities, which contributes to the representation of qualitatively different experiences. The basis for identification of modalities is proposed to be constituted by self-organized comparative operations across a network of unimodal and multimodal sensory areas. However, such network interactions alone cannot answer the question how sensory feature detectors collectively account for an integrated, yet phenomenally differentiated experiential content. This problem turns out to be different from, although related to, the binding problem. It is proposed that the neural correlate of an enriched, multimodal experience is constituted by the attractor state of a dynamic associative network. Within this network, unimodal and multimodal sensory maps continuously interact to influence each other’s attractor state, so that a feature change in one modality results in a fast re-coding of feature information in another modality. In this scheme, feature detection is coded by firing-rate, whereas firing phase codes relational aspects.     

Experience-dependent alterations in conscious resting state activity following perceptuomotor learning

In monkeys and rats, neural activity patterns during learning are reactivated during subsequent periods of rest or sleep. According to the reactivation–consolidation account, this process underlies the consolidation of memories. Brain imaging studies have extended these findings to humans during sleep, but not yet, during rest. Here, we show that learning-related reactivation also occurs in humans during rest. During functional MRI-scanning, participants trained on a perceptuomotor task flanked by rest periods. During training, we found robust activity in the superior parietal cortex. During post-training rest, this same area reactivated. We also found a link between parietal reactivation and learning. Activity in superior parietal cortex was associated with learning during training, and a control group that did not train on the perceptuomotor task did not show any difference between the pre- and post-training rest blocks in this region. These findings indicate that, during rest, reactivation also occurs in humans. This process may contribute to consolidation of perceptuomotor memories.