Neurosteroid Biosynthesis Regulates Sexually Dimorphic Fear and Aggressive Behavior in Mice

Abstract

The neurosteroid allopregnanolone is a potent positive allosteric modulator of GABA action at GABA(A) receptors. Allopregnanolone is synthesized in the brain from progesterone by the sequential action of 5alpha-reductase type I (5alpha-RI) and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). 5alpha-RI and 3alpha-HSD are co-expressed in cortical, hippocampal, and olfactory bulb glutamatergic neurons and in output neurons of the amygdala, thalamus, cerebellum, and striatum. Neither 5alpha-RI nor 3alpha-HSD mRNAs is expressed in glial cells or in cortical or hippocampal GABAergic interneurons. It is likely that allopregnanolone synthesized in principal output neurons locally modulates GABA(A) receptor function by reaching GABA(A) receptor intracellular sites through lateral membrane diffusion. This review will focus on the behavioral effects of allopregnanolone on mouse models that are related to a sexually dimorphic regulation of brain allopregnanolone biosynthesis. Animal models of psychiatric disorders, including socially isolated male mice or mice that receive a long-term treatment with anabolic androgenic steroids (AAS), show abnormal behaviors such as altered fear responses and aggression. In these animal models, the cortico-limbic mRNA expression of 5alpha-RI is regulated in a sexually dimorphic manner. Hence, in selected glutamatergic pyramidal neurons of the cortex, CA3, and basolateral amygdala and in granular cells of the dentate gyrus, mRNA expression of 5alpha-RI is decreased, which results in a downregulation of allopregnanolone content. In contrast, 5alpha-RI mRNA expression fails to change in the striatum medium spiny neurons and in the reticular thalamic nucleus neurons, which are GABAergic.By manipulating allopregnanolone levels in glutamatergic cortico-limbic neurons in opposite directions to improve [using the potent selective brain steroidogenic stimulant (SBSS) S-norfluoxetine] or induce (using the potent 5alpha-RI inhibitor SKF 105,111) behavioral deficits, respectively, we have established the fundamental role of cortico-limbic allopregnanolone levels in the sexually dimorphic regulation of aggression and fear. By selectively targeting allopregnanolone downregulation in glutamatergic cortico-limbic neurons, i.e., by improving the response of GABA(A) receptors to GABA, new therapeutics would offer appropriate and safe management of psychiatric conditions, including impulsive aggression, irritability, irrational fear, anxiety, posttraumatic stress disorders, and depression.

Role of Social Encounter-Induced Activation of Prefrontal Serotonergic Systems in the Abnormal Behaviors of Isolation-Reared Mice

“…Furthermore, we demonstrated that the encounter with the sleeping intruder or exposure to a novel object did not increase locomotor activity in male isolation-reared mice ( Figure 4a). As social isolation does not induce aggressive behavior in female mice (Pinna et al, 2003(Pinna et al, , 2005(Pinna et al, , 2008, the present findings indicate that encounter-induced behavioral responses to emotional states, such as anxiety or fear, are observed selectively in male isolation-reared mice.…”

“…However, the mice were able to see, hear, and smell their neighbor. Thus, a social encounter with an unfamiliar conspecific through a mesh partition is considered a form of psychological stress, and it is useful for studies of the neurochemical changes that may be involved in the abnormal behaviors of isolation-reared animals (Ago et al, 2012;Fone and Porkess, 2008;Lukkes et al, 2009a, b;Pinna et al, 2008). In this study, the total time that the resident mice spent near the partition and the total time the resident and intruder mice spent interacting did not differ between the male group-reared, female isolation-reared, and male isolation-reared mice (Figure 1c).…”

“…We used c-Fos expression to measure regional changes in brain activity (Koda et al, 2010;Kovács, 2008). As a control, we further examined female isolationreared mice, because they do not develop hyper-aggression, unlike male isolation-reared mice (Pinna et al, 2005(Pinna et al, , 2008.…”

Stability of Tilo® tablets formulation obtained from dry extract of Justice pectoralis Jacq.

“…The Open field activity was carried out according to a previously reported method with some modifications (Archer, 1977;Walsh, Cummins, 1976;Pinna et al, 2008). Thirty minutes after the administration of vehicle or test compound, a mouse was placed in the centre of a round open field of 30 cm diameter and 25 cm high, and the open field activity were measured during 6 minutes recording how many times the animal stays in the centre of the cage and the number of risings.…”

“…This study was realized according to the method described by Pinna et al (2008). A group of animals was isolated in individual cage and other group remained grouped during six week.…”