| Title |
Neurosteroid Biosynthesis Regulates Sexually Dimorphic Fear and Aggressive Behavior in Mice
|
|---|---|
| Published in |
Neurochemical Research, May 2008
|
| DOI | 10.1007/s11064-008-9718-5 |
| Pubmed ID | |
| Authors |
Graziano Pinna, Roberto Carlos Agis-Balboa, Fabio Pibiri, Marianela Nelson, Alessandro Guidotti, Erminio Costa |
| 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. |
Mendeley readers
The data shown below were compiled from readership statistics for 99 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 1 | 1% |
| Japan | 1 | 1% |
| Unknown | 97 | 98% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 24 | 24% |
| Student > Master | 15 | 15% |
| Researcher | 9 | 9% |
| Professor | 9 | 9% |
| Student > Postgraduate | 6 | 6% |
| Other | 24 | 24% |
| Unknown | 12 | 12% |
| Readers by discipline | Count | As % |
|---|---|---|
| Neuroscience | 19 | 19% |
| Agricultural and Biological Sciences | 19 | 19% |
| Psychology | 15 | 15% |
| Medicine and Dentistry | 12 | 12% |
| Biochemistry, Genetics and Molecular Biology | 12 | 12% |
| Other | 7 | 7% |
| Unknown | 15 | 15% |
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 June 2022.
All research outputs
#7,453,126
of 22,785,242 outputs
Outputs from Neurochemical Research
#589
of 2,094 outputs
Outputs of similar age
#27,413
of 78,096 outputs
Outputs of similar age from Neurochemical Research
#7
of 22 outputs
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