Synergistic effects of early life mild adversity and chronic social defeat on rat brain microglia and cytokines.

Exposure to early life stress affects the development and function of the brain and when followed by adversities in adulthood, the negative effects of stress are enhanced. Microglia has been proposed as a potential mediator of this phenomenon. In the present study, we investigated the long-term effects of mild early life stress, the consequences of a stressor in adulthood as well as their interaction on microglial and cytokine (PPARγ, IL-1β and TNFα) levels in the brain of adult male rats.

A Fear Memory Engram and Its Plasticity in the Hypothalamic Oxytocin System.

Oxytocin (OT) release by axonal terminals onto the central nucleus of the amygdala exerts anxiolysis. To investigate which subpopulation of OT neurons contributes to this effect, we developed a novel method: virus-delivered genetic activity-induced tagging of cell ensembles (vGATE). With the vGATE method, we identified and permanently tagged a small subpopulation of OT cells, which, by optogenetic stimulation, strongly attenuated contextual fear-induced freezing, and pharmacogenetic silencing of tagged OT neurons impaired context-specific fear extinction, demonstrating that the tagged OT neurons are sufficient and necessary, respectively, to control contextual fear.

Deciphering the Contributions of CRH Receptors in the Brain and Pituitary to Stress-Induced Inhibition of the Reproductive Axis.

Based on pharmacological studies, corticotropin-releasing hormone (CRH) and its receptors play a leading role in the inhibition of the hypothalamic-pituitary-gonadal (HPG) axis during acute stress. To further study the effects of CRH receptor signaling on the HPG axis, we generated and/or employed male mice lacking CRH receptor type 1 (CRHR1) or type 2 (CRHR2) in gonadotropin-releasing hormone neurons, GABAergic neurons, or in all central neurons and glia. The deletion of CRHRs revealed a preserved decrease of plasma luteinizing hormone (LH) in response to either psychophysical or immunological stress.

Oxytocin and Pain Perception: From Animal Models to Human Research.

An accumulating body of evidence suggests that the hypothalamic neuropeptide oxytocin (OT) has a modulatory effect on pain processing. Particularly strong evidence comes from animal models. Here, we review recent advances in animal research on the analgesic effects of OT and discuss possible target sites of OT within descending and ascending pain pathways in the brain.

Vasopressin casts light on the suprachiasmatic nucleus.

Key Points: A subpopulation of retinal ganglion cells expresses the neuropeptide vasopressin. These retinal ganglion cells project predominately to our biological clock, the suprachiasmatic nucleus (SCN). Light-induced vasopressin release enhances the responses of SCN neurons to light.

Effects of a Neonatal Experience Involving Reward Through Maternal Contact on the Noradrenergic System of the Rat Prefrontal Cortex.

The noradrenergic system plays an important role in prefrontal cortex (PFC) function. Since early life experiences play a crucial role in programming brain function, we investigated the effects of a neonatal experience involving reward through maternal contact on the noradrenergic system of the rat PFC. Rat pups were exposed during Postnatal days (PNDs) 10-13, to a T-maze in which contact with the mother was used as a reward (RER).

Rat dams exposed repeatedly to a daily brief separation from the pups exhibit increased maternal behavior, decreased anxiety and altered levels of receptors for estrogens (ERα, ERβ), oxytocin and serotonin (5-HT1A) in their brain.

In the present study we investigated the neurobiological mechanisms underlying expression of maternal behavior. Increased maternal behavior was experimentally induced by a brief 15-min separation between the mother and the pups during postnatal days 1 to 22. On postnatal days (PND) 12 and 22, we determined in experimental and control dams levels of anxiety in the elevated plus maze (EPM) as well as the levels of receptors for estrogens (ERα, ERβ), oxytocin (OTR) and serotonin (5-HT1AR) in areas of the limbic system (prefrontal cortex-PFC, hippocampus, lateral septum-SL, medial preoptic area-MPOA, shell of nucleus accumbens-nAc-Sh, central-CeA and basolateral-BLA amygdala), involved in the regulation of maternal behavior.

A novel model of early experiences involving neonatal learning of a T-maze using maternal contact as a reward or its denial as an event of mild emotional adversity.

We developed a novel animal model of early life experiences in which rat pups are trained during postnatal days (PND) 10-13 in a T-maze with maternal contact as a reward (RER group) or its denial (DER group) as a mildly aversive event. Both groups of animals learn the T-maze, albeit the RER do so more efficiently. Training results in activation of the basal ganglia in the RER and of the hippocampus and prefrontal cortex in the DER.

Effects of an early experience of reward through maternal contact or its denial on the dopaminergic system of the rat brain.

The mesolimbic/mesocortical dopaminergic pathway plays a pivotal role in the reward system. During the neonatal period the mother is the main source of rewarding stimuli. We have developed an experimental model in which rat pups learn a T-maze during the neonatal period (postnatal day (PND) 10-13) using contact with the mother as the reward.

Denial or receipt of expected reward through maternal contact during the neonatal period differentially affect the development of the rat amygdala and program its function in adulthood in a sex-dimorphic way.

Early experiences affect brain development and thus adult brain function and behavior. We employed a novel early experience model involving denial (DER) or receipt of expected reward (RER) through maternal contact in a T-maze. Exposure to the DER experience for the first time, on postnatal day 10 (PND10), was stressful for the pups, as assessed by increased corticosterone levels, and was accompanied by enhanced activation of the amygdala, as assessed by c-Fos immunohistochemistry.

Effects of an early experience of reward through maternal contact or its denial on laterality of protein expression in the developing rat hippocampus.

Laterality is a basic characteristic of the brain which is detectable early in life. Although early experiences affect laterality of the mature brain, there are no reports on their immediate neurochemical effects during neonatal life, which could provide evidence as to the mechanisms leading to the lateralized brain. In order to address this issue, we determined the differential protein expression profile of the left and right hippocampus of 13-day-old rat control (CTR) pups, as well as following exposure to an early experience involving either receipt (RER) or denial (DER) of the expected reward of maternal contact.

Effects of denial of reward through maternal contact in the neonatal period on adult hypothalamic-pituitary-adrenal axis function in the rat.

Emotional behavioral traits associated with stress response are well documented to be affected by early life events. In the present work, we used a novel paradigm of neonatal experience, in which pups were trained in a T-maze and either received (RER rats) or were denied (DER) the reward of maternal contact, during postnatal days 10-13. We then evaluated stress coping and key factors controlling the function of the hypothalamic-pituitary-adrenal axis in adulthood.

Denial of reward in the neonate shapes sociability and serotonergic activity in the adult rat.

Background: Manipulations of the early environment are linked to long-lasting alterations of emotionality and social capabilities. Denial of rewarding mother-pup interactions in early life of rats could serve as model for child neglect. Negative consequences for social competence in later life, accompanied by changes in the serotonergic system would be expected.

Effects of interaction of an early experience of reward through maternal contact or its denial with social stress during adolescence on the serotonergic system and the stress responsiveness of adult female rats.

Experiences during critical periods, such as the neonatal and adolescence, play a critical role in determining adult stress-coping behavior. Based on the aforementioned we developed an experimental protocol, which included a neonatal experience and a social stress during adolescence. The serotonergic system is known as an important modulator of coping ability and, in general, emotional balance in both normal and pathological states, such as depression and anxiety, for which females are more vulnerable.

Effect of neonatal handling on adult rat spatial learning and memory following acute stress.

Brief neonatal handling permanently alters hypothalamic-pituitary-adrenal axis function resulting in increased ability to cope with stress. Since stress is known to affect cognitive abilities, in the present study we investigated the effect of brief (15 min) handling on learning and memory in the Morris water maze, following exposure to an acute restraint stress either before training or recall. Exposure of non-handled rats to the acute stress prior to training resulted in quicker learning of the task, than in the absence of the stressor.