T3 is linked to stress-associated reduction of prolactin in lactating women.

The relationship between stress responses and lactation is bidirectional. Breastfeeding confers many benefits to maternal health, including attenuated hypothalamic-pituitary-adrenal axis responsiveness to stress. However, increased stress burden can impair lactation. The mechanisms that underlie these relationships are poorly understood. The present study aimed to compare breastfeeding habits, as well as subjective and objective measures of stress, in employed and non-employed lactating women and assess the relationships between these measures and prolactin (PRL), thyroid hormones (thyroid-stimulating hormone, triiodothyronine [T3] and thyroxine), vasopressin and cortisol levels. A dexamethasone suppression test was also administered to determine the sensitivity of the hypothalamic-pituitary-adrenal axis to negative-feedback. We report that lactating employed women had lower breastfeeding rates and lower PRL than lactating non-employed women. They also had a significantly higher stress burden, indicated by elevations in blood pressure and evening cortisol, relative to lactating non-employed women. In regression analyses that controlled for feeding modality and breastfeeding duration, we found these factors differentially affected PRL in the two groups and there were significant differences in PRL across groups that were not accounted for by these factors. A mediation regression analysis suggested that group differences in PRL were best explained by differences in T3 and income levels, rather than breastfeeding duration or other variables. Our data fit a speculative model in which elevated maternal stress increases cortisol, which suppresses T3, leading to decreased PRL. The decreases in PRL are associated with higher rates of bottlefeeding, which may further contribute to decreased PRL.

Peptide-Liganded G Protein-Coupled Receptors as Neurotherapeutics.

Peptide-liganded G protein-coupled receptors (GPCRs) are a growing fraction of GPCR drug targets, concentrated in two of the five major GPCR structural classes. The basic physiology and pharmacology of some within the rhodopsin class, for example, the enkephalin (µ opioid receptor, MOR) and angiotensin (ATR) receptors, and most in class B, all the members of which are peptide receptors, are well-known, whereas others are less so. Furthermore, with the notable exception of opioid peptide receptors, the ability to translate from peptide to "drug-like" (i.e., low-molecular-weight nonpeptide) molecules, with desirable oral absorption, brain penetrance, and serum stability, has met with limited success. Yet, peripheral peptide administration in patients with metabolic disorders is clinically effective, suggesting that "drug-like" molecules for peptide receptor targets may not always be required for disease intervention. Here, we consider recent developments in GPCR structure analysis, intracellular signaling, and genetic analysis of peptide and peptide receptor knockout phenotypes in animal models. These lines of research converge on a better understanding of how peptides facilitate adaptive behaviors in mammals. They suggest pathways to translate this burgeoning information into identified drug targets for neurological and psychiatric illnesses such as obesity, addiction, anxiety disorders, and neurodegenerative diseases. Advances centered on the peptide ligands oxytocin, vasopressin, GLP-1, ghrelin, PACAP, NPY, and their GPCRs are considered here. These represent the spectrum of progress across the "virtual pipeline", of peptide receptors associated with many established drugs, those of long-standing interest for which clinical application is still under development, and those just coming into focus through basic research.

Environmental enrichment prevents acute restraint stress-induced anxiety-related behavior but not changes in basolateral amygdala spine density.

Previous studies showed that acute restraint stress or transient elevation of glucocorticoid (GC) stress hormones produces emergent changes in both anxiety behavior and dendritic branches in the basolateral amygdala complex (BLA) of rats. In this work, we demonstrate that exposure to environmental enrichment (EE) prevented stress-induced increases in anxiety (emerging 10 days post-stress) in adult rats without blocking stress-induced dendritic branch remodeling in the BLA nor stress-induced enhancement of GC serum levels.

Tracking the Time-Dependent Role of the Hippocampus in Memory Recall Using DREADDs.

The hippocampus is critical for the storage of new autobiographical experiences as memories. Following an initial encoding stage in the hippocampus, memories undergo a process of systems-level consolidation, which leads to greater stability through time and an increased reliance on neocortical areas for retrieval. The extent to which the retrieval of these consolidated memories still requires the hippocampus is unclear, as both spared and severely degraded remote memory recall have been reported following post-training hippocampal lesions. One difficulty in definitively addressing the role of the hippocampus in remote memory retrieval is the precision with which the entire volume of the hippocampal region can be inactivated. To address this issue, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), a chemical-genetic tool capable of highly specific neuronal manipulation over large volumes of brain tissue. We find that remote (>7 weeks after acquisition), but not recent (1-2 days after acquisition) contextual fear memories can be recalled after injection of the DREADD agonist (CNO) in animals expressing the inhibitory DREADD in the entire hippocampus. Our data demonstrate a time-dependent role of the hippocampus in memory retrieval, supporting the standard model of systems consolidation.

Adenosine A2A Receptors in the Amygdala Control Synaptic Plasticity and Contextual Fear Memory.

The consumption of caffeine modulates working and reference memory through the antagonism of adenosine A2A receptors (A2ARs) controlling synaptic plasticity processes in hippocampal excitatory synapses. Fear memory essentially involves plastic changes in amygdala circuits. However, it is unknown if A2ARs in the amygdala regulate synaptic plasticity and fear memory. We report that A2ARs in the amygdala are enriched in synapses and located to glutamatergic synapses, where they selectively control synaptic plasticity rather than synaptic transmission at a major afferent pathway to the amygdala. Notably, the downregulation of A2ARs selectively in the basolateral complex of the amygdala, using a lentivirus with a silencing shRNA (small hairpin RNA targeting A2AR (shA2AR)), impaired fear acquisition as well as Pavlovian fear retrieval. This is probably associated with the upregulation and gain of function of A2ARs in the amygdala after fear acquisition. The importance of A2ARs to control fear memory was further confirmed by the ability of SCH58261 (0.1 mg/kg; A2AR antagonist), caffeine (5 mg/kg), but not DPCPX (0.5 mg/kg; A1R antagonist), treatment for 7 days before fear conditioning onwards, to attenuate the retrieval of context fear after 24-48 h and after 7-8 days. These results demonstrate that amygdala A2ARs control fear memory and the underlying process of synaptic plasticity in this brain region. This provides a neurophysiological basis for the association between A2AR polymorphisms and phobia or panic attacks in humans and prompts a therapeutic interest in A2ARs to manage fear-related pathologies.

Hippocampal regulation of aversive memories.

For many years, the hippocampal formation has been implicated in the regulation of negative emotion, yet the nature of this link has remained elusive. Recent studies have made important links between the hippocampus and regulation of stress hormones that affect aversive memory. Additional studies have shown that the hippocampus regulates the gating of fear by contextual information. An emerging literature also links the hippocampus to prediction errors during fear learning and extinction. The mechanisms by which the hippocampus regulates negative emotion are clearly complicated, but suggest that interventions aimed at restoring normal hippocampal function may help with disorders of negative affect, such as depression or post-traumatic stress disorder and depression.

Changes in brain MicroRNAs contribute to cholinergic stress reactions.

Mental stress modifies both cholinergic neurotransmission and alternative splicing in the brain, via incompletely understood mechanisms. Here, we report that stress changes brain microRNA (miR) expression and that some of these stress-regulated miRs regulate alternative splicing. Acute and chronic immobilization stress differentially altered the expression of numerous miRs in two stress-responsive regions of the rat brain, the hippocampal CA1 region and the central nucleus of the amygdala. miR-134 and miR-183 levels both increased in the amygdala following acute stress, compared to unstressed controls. Chronic stress decreased miR-134 levels, whereas miR-183 remained unchanged in both the amygdala and CA1. Importantly, miR-134 and miR-183 share a common predicted mRNA target, encoding the splicing factor SC35. Stress was previously shown to upregulate SC35, which promotes the alternative splicing of acetylcholinesterase (AChE) from the synapse-associated isoform AChE-S to the, normally rare, soluble AChE-R protein. Knockdown of miR-183 expression increased SC35 protein levels in vitro, whereas overexpression of miR-183 reduced SC35 protein levels, suggesting a physiological role for miR-183 regulation under stress. We show stress-induced changes in miR-183 and miR-134 and suggest that, by regulating splicing factors and their targets, these changes modify both alternative splicing and cholinergic neurotransmission in the stressed brain.