60 YEARS OF NEUROENDOCRINOLOGY: Redefining neuroendocrinology: stress, sex and cognitive and emotional regulation

Abstract

The discovery of steroid hormone receptors in brain regions that mediate every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. This imbalance, in turn, affects systemic physiology via neuroendocrine, autonomic, immune and metabolic mediators. In the short term, as for increased fearful vigilance and anxiety in a threatening environment, these changes may be adaptive. But, if the danger passes and the behavioral state persists along with the changes in neural circuitry, such maladaptation may need intervention with a combination of pharmacological and behavioral therapies, as is the case for chronic anxiety and depression. There are important sex differences in the brain responses to stressors that are in urgent need of further exploration. Moreover, adverse early-life experience, interacting with alleles of certain genes, produce lasting effects on brain and body over the life-course via epigenetic mechanisms. While prevention is most important, the plasticity of the brain gives hope for therapies that take into consideration brain-body interactions.

Keywords: behaviour; brain; hormone action; neuroendocrinology; stress hormones.

Figure 1

The hippocampal formation is a target of adrenocortical steroids and is involved in spatial and episodic memory, as well as mood regulation. Both pyramidal neurons in Ammon’s horn and neurons of the dentate express Type I or mineralocorticoid (MR) and Type 2 or glucocorticoid (GR) receptors.

Figure 2

The hippocampal formation is activated in spatial memory as in the London Cab Driver’s study (Maguire et al 1997), as well as in spatial location of food in food-caching birds and squirrels (see text). The hippocampus is also a target of sex hormones that affect spatial memory (Sandstrom & Williams 2004). The hippocampus is also sensitive to damage by seizures, ischemia and head trauma in which glucocorticoids synergize effects of excitatory amino acid overload (Sapolsky 1990).

Figure 3

Four peptide/protein hormones, insulin- like growth factor I (IGF-I), insulin, ghrelin, and leptin, are able to enter the brain and affect structural remodeling or other functions in the hippocampus. A transport process is involved, and specific receptors are expressed in hippocampus, as well as in other brain regions. Molecular sizes are indicated for each hormone in kiloDaltons (kDa): ghrelin, 3.5 kDa; leptin, 16 kDa; insulin, 5.8 kDa; IGF-I, 7.6 kDa. Reprinted from (McEwen 2007).

Figure 4

The Stress Response and Development of Allostatic Load. The perception of stress is influenced by one’s experiences, genetics, and behavior. When the brain perceives an experience as stressful, physiologic and behavioral responses are initiated, leading to allostasis and adaptation. Over time, allostatic load can accumulate, and the overexposure to mediators of neural, endocrine, and immune stress can have adverse effects on various organ systems, leading to disease. Reprinted from (McEwen 1998).

Figure 5

The trisynaptic organization of the hippocampus showing input from the entorhinal cortex to both CA3 and dentate gyrus (DG), with feed forward and feedback connections between these two regions that promotes memory formation in space and time but, at the same time, makes the CA3 vulnerable to seizure-induced excitatory (McEwen 1999). Chronic stress causes apical dendrites of CA3 neurons to debranch and shorten in a reversible manner, and glutamate release by giant mossy fiber terminals is a driving force. Chronic stress also inhibits neurogenesis in DG and can eventually reduce DG neuron number and DG volume.

Figure 6

Cyclic ovarian function regulates spine synapse turnover in the CA1 regions of the rat hippocampus and it does so via a combination of nuclear and non-nuclear estrogen receptors. The cell nuclear estrogen receptors are found in a subset of inhibitory interneurons whereas the non-nuclear receptors are expressed in presynaptic cholinergic and NPY terminals, in dendrites and mitochondria (Ledoux et al 2009, McEwen & Milner 2007, Nilsen et al 2007).

Figure 7

Glucocorticoids produce both direct and indirect genomic effects, and actions via translocation into mitochondria, as well as direct stimulation of presynaptic glutamate release and other non-genomic actions via signaling pathways that activate endocannabinoid synthesis.

Figure 8

Non-genomic effects of estrogen. Estrogen initiates a complex set of signal transduction pathways in the hippocampal neuron via several membrane-bound receptors. Above are two examples of estrogen-initiated signal transduction leading to spinogenesis and changes in synapse size. Rapid activation of Akt (protein kinase B) via PI3K is thought to be mediated by ER_. Subsequently, activated Akt initiates translation of PSD-95 by removing the repression of the initiation factor 4E–binding protein1 (4E–BP1). Estradiol-mediated phosphorylation of cofilin has been shown to occur via activation of LIMK. Cofilin is an actin depolymerization factor and it is inactivated by phosphorylation. Therefore, in the presence of estrogen, cofilin repression of actin polymerization is removed, resulting in an increase in filopodial density. The signal transduction pathways illustrated here are an oversimplification of a large body of work done in an in vitro cell line. Reprinted from (Dumitriu et al 2010) by permission.

Figure 9

Effects of stress and acute glucocorticoid treatment on gene expression in hippocampus. A. Naïve and 21d chronically restraint stressed (CRS) rats respond differently to a 6h bolus of corticosterone in which more than half of the genes turned on or turned off are different (Datson et al 2013). B. Naïve mice given acute forced swim stress (FST) show a largely different pattern of gene expression (up and down) from naïve mice given an acute corticosterone bolus. Moreover, mice that are either naïve, or 21d CRS or 21d CRS plus 21d recovery respond, in large, differently to acute FST with respect to gene expression levels. There is a core of genes that always respond to the acute FST. (Gray et al 2014).

Figure 10

Novel mechanisms for rapidly acting medications to treat stress-related disorders. a, The novel antidepressant candidate acetyl-L-carnitine (LAC) may act inside and outside the nucleus to exert fast antidepressant responses: it has been shown that LAC corrects mGlu2 deficits in vulnerable animal models by increasing acetylation of either the histone H3K27 bound to Grm2 promoter gene or the NFkB-p65 member (Nasca et al 2013) b, The use of the light-dark test as a screening method allows identification of clusters of animals with a different baseline susceptibility along with differences in mineralocorticoid receptor (MR) levels in hippocampus. The susceptible mice that are characterized by higher baseline MR levels show reduced hippocampal mGlu2 expression associated with exacerbation of anxious and of depressive-like behaviors after acute and chronic stress, respectively. Conversely, individuals with lower baseline MR levels cope better with stress and show adaptation in mGlu2 receptor expression in hippocampus. The epigenetic allostasis model points to the developmental origins of these individual differences, suggesting that unknown epigenetic influences early in life may lead to alterations in MR hippocampal levels (Nasca et al 2014)