Gonadectomy in adult life increases tyrosine hydroxylase immunoreactivity in the prefrontal cortex and decreases open field activity in male rats

doi:10.1016/S0306-4522(98)00341-8

Neuroscience

Volume 89, Issue 3, March 1999, Pages 939-954

https://doi.org/10.1016/S0306-4522(98)00341-8 Get rights and content

Abstract

The prefrontal cortices in rats participate in a range of cognitive, emotional, and locomotor functions that are dependent on its rich catecholamine innervation. Sex differences identified in many of these functions suggest that the prefrontal cortex is also influenced by gonadal hormones. Previous studies have shown that prefrontal catecholamines can be modified by changes in the hormone environment in developing animals. The present analyses, carried out in male rats gonadectomized as adults, with and without supplementation with testosterone proprionate, and examined at intervals from two days to 10 weeks after surgery, revealed that both the anatomical organization of prefrontal catecholamine afferents, and a behavioral measure sensitive to their selective lesioning remain highly responsive to changes in testicular hormones in adulthood. Thus, gonadectomy in adult male rats rapidly led to a large but transient decrease in the density of tyrosine hydroxylase immunoreactivity in all layers of the dorsal anterior cingulate cortex. This was followed by a sustained period in which immunoreactivity in the supragranular layers returned to levels that were just below normal (between 72 and 79% of normal), and labeling in deep laminae stabilized at considerably elevated innervation densities (approximately 150% of normal). Neither the acute decrease nor the chronic over-innervation characteristic of gonadectomized animals was observed in rats that were gonadectomized and supplemented with testosterone proprionate. Open field activity assessed along a corresponding 10 week timeline showed that gonadectomized animals were significantly less active than hormonally intact controls, a behavioral pattern opposite to the hyperactivity which persists following prefrontal dopamine lesions. Gonadectomized animals supplemented with testosterone proprionate, on the other hand, had open field scores that were not significantly different from controls.

Taken together, these findings indicate that the adult hormone environment provides a significant, and seemingly functionally significant influence over the catecholamine innervation of the rat prefrontal cortex. Such lifelong responsiveness of the prefrontal cortical catecholamines to circulating hormones suggests that gonadal steroids are an active component of the biology of normal adult cognition, and may also have relevance for cortical dysfunction in disorders such as schizophrenia which are not only strongly tied to the catecholamines, but exhibit considerable biases among men and women as well.

Section snippets

Animal subjects

Ninety-seven adult male Sprague–Dawley rats (Taconic Farms, Germantown, NY) were used. All procedures involving animals are approved by the Institutional Animal Care and Use Committee, SUNY at Stony Brook, and minimize the use of animals and their discomfort. In initial anatomical studies, five sham-operated and five gonadectomized animals were examined at each of seven post-surgical time-points. Two additional cohorts of animals were used to analyse the anatomical effects of acute and chronic

Efficacy of hormone treatments

The surgical procedures and hormone replacement methods used in this study have been utilized in numerous investigations to reduce and restore physiological levels of circulating testicular hormones.[12]The efficacy of these methods was confirmed in this study by weighing the androgen-sensitive bulbospongiosus muscles (Table 1). This measure is a proven, sensitive assay for circulating androgens in rats.[70]Similar to previous results,[12]bulbospongiosus muscle mass was less than control

Discussion

Prefrontal cortical functioning in rats, monkeys and man show striking sex differences. The hormone influence suggested in these may hold significance both for the biology of complex cognitive functions, and for the prefrontal cortical dysfunction seen in disorders such as schizophrenia which often show sex differences in incidence, course or outcome.24, 56The present evaluation of TH immunoreactivity in the prefrontal cortex of hormonally intact, gonadectomized and gonadectomized and

Conclusions

The present analyses, carried out in male rats gonadectomized as adults, with and without supplementation with testosterone proprionate, and examined two days to 10 weeks after surgery, revealed that both the anatomical organization of prefrontal catecholamine afferents, and a behavioral measure sensitive to their selective lesioning remain highly responsive to changes in testicular hormones in adulthood. This hormone modifiability of prefrontal catecholamines and the possibility for behavioral

Acknowledgements

This work was supported in part by a Dean's Grant, SUNY at Stony Brook School of Medicine (MFK) and by a FIRST Award R29NS35422 (MFK).

References (79)

E Battaner et al.
Gonadal influences on spinal cord and brain monoamines in male rats
Brain Res.
(1987)
B Berger et al.
Dopaminergic innervation of the cerebral cortex: unexpected differences between rodents nad primates
Trends Neurosci.
(1991)
B Berger et al.
New dopaminergic terminal fields in the motor and retrosplenial cortex in the young and adult rat. Immunocytochemical and catecholamine histochemical analyses
Neuroscience
(1985)
B Berger et al.
Postnatal ontogenesis of the dopaminergic innervation in the rat anteior cingulate cortex (area 24). Immunocytochemical and catecholamine fluorescence histochemical analysis
Devl Brain Res.
(1985)
J.D Blaustein et al.
Immunocytochemical localization of estrogen-induced progestin receptors in guinea pig brain
Brain Res.
(1988)
D.A Blizard et al.
Sex differences in open-field behavior in the rat: the inductive and activational role of gonadal hormones
Physiol. Behav.
(1975)
P.M Bronstein et al.
Sex-related differences in rats' open-field activity
Behav. Biol.
(1975)
C.J Carter et al.
Behavioural and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat
Brain Res.
(1980)
W.F Collins et al.
Differential effect of castration on the somal size of pudenal motoneurons in the adult male rat
Brain Res.
(1992)
B Costall et al.
The behavioral effects of dopamine applied intracerebrally to areas of the mesolimbic system
Eur. J. Pharmac.
(1975)

J.L.M Dawson et al.

Developmental effects of neonatal sex hormones on spatial activity skills in the white rat

Biol. Psychol.

(1975)

J.P.C DeBruin et al.

Behavioral changes following lesions of the orbital prefrontal cortex in male rats

Behav. Brain Res.

(1983)

L Descarries et al.

Regional and laminar density of the dopamine innervation in adult rat cerebral cortex

Neuroscience

(1987)

A DuPont et al.

Effects of chronic estrogen treatment on dopamine concentrations and turnover in discrete brain nuclei of ovariectomized rats

Neurosci. Lett.

(1981)

P.C Emson et al.

The origin and distribution of dopamine-containing afferents to the rat prefrontal cortex

Brain Res.

(1978)

S.C Gerson et al.

Motor effects of serotonin in the central nervous system

Life Sci.

(1980)

K Hagihara et al.

Distribution of cells containing progesterone receptor mRNA in the female rat di- and telencephalon: an in situ hybridization study

Molec. Brain Res.

(1992)

E Hampson

Variaitons in sex-related cognitive abilities across the menstrual cycle

Brain Cogn.

(1990)

T Hokfelt et al.

Pharmacohistochemical evidence of the existence of dopamine nerve terminals in the limbic cortex

Eur. J. Pharmac.

(1974)

R.R Holson et al.

Mesial prefrontal cortical lesions and timidity in rats. II. Reactivity to novel stimuli

Physiol. Behav.

(1986)

J.M Joffe et al.

Effects of weaning age and adult handling on avoidance conditioning, open-field behavior, and plasma corticosterone of adult rats

Behav. Biol.

(1973)

A Kalsbeek et al.

Ontogeny of open field activity in rats after neonatal lesioning of the mesocortical dopaminergic projection

Behav. Brain Res.

(1989)

B Kolb

Functions of the frontal cortex in the rat: a comparative review

Brain Res. Rev.

(1984)

O Lindvall et al.

Organization of catecholamine neurons projecting to the frontal cortex in the rat

Brain Res.

(1978)

V.N Luine et al.

Effect of 17β estradiol on hypothalamic tyrosine hydroxylase activity

Brain Res.

(1977)

J.A Munoz-Cueto et al.

Regional sex differences in spine density along the apical shaft of visual cortex pyramids during postnatal development

Brain Res.

(1991)

D.L Rosin et al.

Effects of 6-hydroxydopamine lesions of the prefrontal cortex on tyrosine hydroxylase activity in subcortical dopamine systems of the rat

Neuroscience

(1992)

P Seymoure et al.

Sex differences in cortical thickness and the dendritic tree in the monocular and binocular subfields of the rat visual cortex at weaning age

Devl Brain Res.

(1992)

R.B Simerly

Hormonal control of the development and regulation of tyrosine hydroxylase expression within a sexually dimorphic population of dopaminergic cells in the hypothalamus

Molec. Brain Res.

(1989)

A.K Slob et al.

Effects of gonadectomy and exogenous gonadal steriods on sex differnces in open field behavior of adult rats

Behav. Brain Res.

(1981)

J Stewart et al.

Estradiol derived from testosterone in prenatal life affects the development of catecholamine systems in the frontal cortex in the male rat

Brain Res.

(1994)

J Stewart et al.

Effects of neonatal androgen on open field and maze learning in the prepubescent and adult rat

Physiol. Behav.

(1975)

J.P Tassin et al.

Differential effects of a two-minute open field session on dopamine utilization in the frontal cortices of BALB/C and C57 BL/6 mice

Neurosci. Lett.

(1980)

J.P Tassin et al.

Relationship between the locomotor hyperactivity induced by A10 lesions and the destruction of the fronto-cortical dopaminergic innervation in the rat

Brain Res.

(1978)

C.G Van Eden et al.

Immunocytochemical localization of dopamine in the prefrontal cortex of the rat at the light and electron microscopical level

Neuroscience

(1987)

M Warembourg et al.

Immunocytochemical localization of progesterone receptors in the guinea pig central nervous system

Brain Res.

(1986)

T.J Brozoski et al.

Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey

Science

(1979)

C.J Carter et al.

Lesions of the frontal cortex of the rat: changes in neurotransmitter systems in subcortical regions

Br. J. Pharmac.

(1978)

A.S Clark et al.

Gonadal hormones influence the emergence of cortical function in nonhuman primates

Behav. Neurosci.

(1989)

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Gonadectomy in adult life increases tyrosine hydroxylase immunoreactivity in the prefrontal cortex and decreases open field activity in male rats

Abstract

Section snippets

Animal subjects

Efficacy of hormone treatments

Discussion

Conclusions

Acknowledgements

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Neuroscience

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Behav. Biol.

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Biol. Psychol.

Behav. Brain Res.

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Neurosci. Lett.

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Br. J. Pharmac.

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Behav. Neurosci.