A neuroanatomical and neurochemical study of the indusium griseum and anterior hippocampal continuation: comparison with dentate gyrus.

The indusium griseum (IG) and anterior hippocampal continuation (AHC) are longitudinal and continuous structures that consist of two narrow strips of gray matter overlying the rostrocaudal length of the corpus callosum, extending rostrally to the genu of the corpus callosum and ventrally to the rostrum. The present study aimed to characterize the phenotype of neuronal innervations to the IG-AHC and their intra-structural topographic organization. Using immunohistochemistry, we found nerve fibers expressing choline acetyltransferase, tyrosine hydroxylase, dopamine-ß-hydroxylase, the serotonin reuptake transporter as well as glutamic acid decarboxylase-67 and parvalbumin. These suggest that the IG and AHC are innervated by acetylcholine, dopamine, noradrenaline, 5-hydroxytryptamine and GABA neurons. More importantly, all these fibers display a topographic laminar distribution in both brain areas. The presence of varicosities along the nerve fibers suggests that these neurotransmitters are released extracellullarly to exert a physiological action. Finally, the structural similarities with the dentate gyrus support the idea that the IG and AHC are anatomically associated, if not continuous, with this area and may represent in mammals a vestige of the hippocampus.

Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine.

Depletion of cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) in adult rats increases the locomotor activating effects of amphetamine. It also impairs sensorimotor gating processes, an effect reversed by the antipsychotic haloperidol. These behavioral effects are suggestive of pronounced hyper-responsiveness of the mesolimbic dopamine (DA) projection to the N.Acc. However, it is unclear whether local cholinergic depletion results predominantly in exaggerated presynaptic DA release or a postsynaptic upregulation of DAergic function. The purpose of the present study is to test the former possibility by employing in vivo voltammetry to examine changes in the levels of extracellular DA within the N.Acc. in response to either mild tail pinch stress or amphetamine administration. While both cholinergic-lesioned and control rats showed reliable stress-induced increases in extracellular DA on two consecutive test days, those in the lesioned rats were significantly less pronounced. In response to amphetamine, a separate cohort of lesioned rats also exhibited smaller increases in extracellular DA release than controls, despite showing greater locomotor activity. Moreover, the increased behavioral response to amphetamine in lesioned rats coincided temporally with decreasing levels of DA in the N.Acc. The results confirm that cholinergic depletion within the N.Acc. suppresses presynaptic DA release and suggest that lesion-induced behavioral effects are more likely due to postsynaptic DA receptor upregulation. The results are also discussed in the context of schizophrenia, where post mortem studies have revealed a selective loss of cholinergic interneurons within the ventral striatum.

Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats.

In rats, selective depletion of the cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) results in heightened behavioural sensitivity to amphetamine and impaired sensorimotor gating processes, suggesting a hyper-responsiveness to dopamine (DA) activity in the N.Acc. We hypothesized that local cholinergic depletion may also trigger distal functional alterations, particularly in prefrontal cortex (PFC). Adult male Sprague-Dawley rats were injected bilaterally in the N.Acc. with an immunotoxin targeting choline acetyltransferase. Two weeks later, cognitive function was assessed using the delayed alternation paradigm in the T-maze. The rats were then implanted with voltammetric recording electrodes in the ventromedial PFC to measure in vivo extracellular DA release in response to mild tail pinch stress. The PFC was also examined for density of tyrosine hydroxylase (TH)-labelled varicosities. In another cohort of control and lesioned rats, we measured post mortem tissue content of DA. Depletion of cholinergic neurons (restricted to N.Acc.) significantly impaired delayed alternation performance across delay intervals. While (basal) post mortem indices of PFC DA function were unaffected by N.Acc. lesions, in vivo mesocortical DA activation was markedly reduced; this deficit correlated significantly with cognitive impairments. TH-labelled varicosities however, were unaffected in cortical layer V relative to controls. These data suggest that selective depletion of cholinergic interneurons in N.Acc. triggers widespread functional impairments in mesocorticolimbic DA function and cognition. The possible relevance of these findings is also discussed in relation to schizophrenia, where reduced density of cholinergic neurons in ventral striatum has been reported.

Sex differences in the effects of perinatal anoxia on dopamine function in rats.

Birth complications involving reduced oxygen to the fetus pose risks for neurodevelopmental disorders like schizophrenia and ADHD, which involve central dopamine (DA) dysfunction and also show gender differences in incidence or severity. Here, we examine possible sex differences in the long-term consequences of perinatal anoxia in the rat, on central DA systems and DA-mediated behaviour. As adults, sensorimotor gating (prepulse inhibition, PPI) was differentially affected by anoxia in males and females, tending to be impaired only in males. Apomorphine-induced suppression of PPI was especially pronounced in males. Anoxia caused increases in amygdala DA levels in both sexes. However, sex-specific changes in DA and metabolite levels in prefrontal cortex and nucleus accumbens were found, suggesting a possible basis for some of the observed gender biases in certain neurodevelopmental disorders, sensitive to birth hypoxia.

Cholinergic depletion in the nucleus accumbens: effects on amphetamine response and sensorimotor gating.

A delicate balance between dopaminergic and cholinergic activity in the ventral striatum or nucleus accumbens (N.Acc) appears to be important for optimal performance of a wide range of behaviours. While functional interactions between these systems are complex, some data suggest that acetylcholine in the N.Acc. may dampen the effects of excessive dopamine (DA) release. We proposed that a reduction in the density of cholinergic interneurons in the N.Acc would result in behavioural alterations suggestive of a hyper-responsiveness of the N.Acc DA system. The present study aimed to produce a sustainable depletion of cholinergic neurons in the N.Acc in the rat and study the effects of such lesions on DA-dependent behaviour. A novel saporin immunotoxin targeting choline acetyltransferase was microinjected bilaterally into the N.Acc of adult rats. We confirmed histologically that two weeks post-injection, animals show a local, selective depletion of cholinergic interneurons (mean cell loss of 44%). Cholinergic-depleted rats showed a marked increase in the locomotor activating effects of amphetamine. In addition, such lesions induced a disruption of sensorimotor gating processes, reflected in a reduction in the prepulse inhibition of the acoustic startle response, which was reversed by haloperidol. These data are suggestive of pronounced hyper-responsiveness of the meso-accumbens DA system which may be of relevance to the pathophysiology of schizophrenia, a condition where selective reduction in the number of ventral striatal cholinergic neurons has been demonstrated.

Lateralized sex differences in stress-induced dopamine release in the rat.

This study examined the possibility that hemispheric differences in stress-induced brain activation vary as a function of sex. Using in-vivo voltammetry, increases in extracellular dopamine release in response to predator odour and tail pinch stress were recorded bilaterally and simultaneously in either the infralimbic cortex or basolateral amygdala. In both stress-sensitive brain regions, significant sex x hemisphere interactions were observed, with males and females showing greater dopamine activation in right-brain and left-brain structures, respectively. Cortical asymmetries in dopamine release also showed sex-specific correlations with stress-induced neuroendocrine activation. Given the intriguing human parallels, we suggest that differential cerebral lateralization may be highly relevant to the disproportionately high incidence of stress-related disorders such as depression and anxiety seen in women.

Sex differences in corticolimbic dopamine and serotonin systems in the rat and the effect of postnatal handling.

Stress-related psychopathology is particularly prevalent in women, although the neurobiological reason(s) for this are unclear. Dopamine (DA) and serotonin (5-HT) systems however, are known to play important adaptive roles in stress and emotion regulation. The aims of the present study included examination of sex differences in stress-related behaviour and neuroendocrine function as well as post mortem neurochemistry, with the main hypothesis that corticolimbic DA and 5-HT systems would show greater functional activity in males than females. Long-Evans rats of both sexes were employed. Additional factors incorporated included differential postnatal experience (handled vs. nonhandled) and adult mild stress experience (acute vs. repeated (5) restraint). Regional neurochemistry measures were conducted separately for left and right hemispheres. Behaviourally, females showed more exploratory behaviour than males in the elevated plus maze and an openfield/holeboard apparatus. Females also exhibited significantly higher levels of adrenocorticotrophic hormone and corticosterone at all time points in response to restraint stress than males across treatment conditions, although both sexes showed similar habituation in stress-induced ACTH activation with repeated mild stress. Neurochemically, females had significantly higher levels of DA (in ventromedial prefrontal cortex (vmPFC), insular cortex and n. accumbens) and 5-HT (in vmPFC, amygdala, dorsal hippocampus and insula) than males. In contrast, males had higher levels of the DA metabolite DOPAC or DOPAC/DA ratios than females in all five regions and higher levels of the 5-HT metabolite 5-HIAA or 5-HIAA/5-HT ratios in vmPFC, amygdala and insula, suggesting greater neurotransmitter utilization in males. Moreover, handling treatment induced a significant male-specific upregulation of 5-HT metabolism in all regions except n. accumbens. Given the adaptive role of 5-HT and DAergic neurotransmission in stress and emotion regulation, the intrinsic sex differences we report in the functional status of these systems across conditions, may be highly relevant to the differential vulnerability to disorders of stress and emotion regulation.

Mesocortical dopamine and HPA axis regulation: role of laterality and early environment.

The infralimbic (IL) cortex is importantly involved in regulating behavioral and physiological responses to stress, including those of the hypothalamic-pituitary-adrenal (HPA) axis. The mesocortical dopamine (DA) system is an important afferent modulator of this region, is highly stress sensitive and frequently shows functional hemispheric asymmetry. Postnatal handling stimulation facilitates development of cortical asymmetry and is also associated with optimal HPA axis regulation. The present study examines the poorly understood role of the mesocortical DA system in regulating HPA axis function in adult rats which were handled (H) or nonhandled (NH) postnatally. In the first experiment, unilateral intra-IL cortex injection of the DA (D1/D2) antagonist alpha-flupenthixol into either hemisphere significantly exaggerated the restraint stress-induced increases in plasma adrenocorticotrophic hormone and corticosterone in NH rats. In H rats, the same effect was lateralized to the right IL cortex. In a second experiment, post mortem neurochemical analysis of DAergic measures in the IL cortex was conducted in H and NH animals following either acute or repeated (5 times) restraint stress. DAergic measures in the right IL cortex were significantly correlated with reduced stress hormone activation in both H and NH rats, especially in repeatedly restrained rats. However, while H rats showed a significant rightward shift in DA metabolism with repeated stress experience, NH rats shifted DA metabolism to the left. It is suggested that, during stress, mesocortical DA release normally acts in an adaptive, negative feedback capacity preventing excessive HPA activation and, with repeated stress, the right IL cortex is particularly important in this capacity. As well, the selective enhancement of DA metabolism in the right IL cortex of H rats may underlie, in part, their typically superior ability to adapt to stress and constrain HPA activity.

What the rodent prefrontal cortex can teach us about attention-deficit/hyperactivity disorder: the critical role of early developmental events on prefrontal function.

The present review surveys a broad range of findings on the functions of the rodent prefrontal cortex (PFC) in the context of the known pathophysiology of attention-deficit/hyperactivity disorder (ADHD). An overview of clinical findings concludes that dysfunction of the right PFC plays a critical role in ADHD and that a number of early developmental factors conspire to increase the risk of the disorder. Rodent studies are described which go far in explaining how the core processes which are deficient in ADHD are mediated by the PFC and that the mesocortical dopamine (DA) system plays a central role in modulating these functions. These studies also demonstrate a surprising degree of cerebral lateralization of prefrontal function in the rat. Importantly, the PFC is highly vulnerable to a wide variety of early developmental insults, which parallel the known risk factors for ADHD. It is suggested that the regulation of physiological and behavioral arousal is a fundamental role of the PFC, upon which many "higher" prefrontal functions are dependent or at least influenced. These right hemispheric arousal systems, of which the mesocortical DA system is a component, are greatly affected by early adverse events, both peri- and postnatally. Abnormal development, particularly of the right PFC and its DAergic afferents, is suggested to contribute directly to the core deficits of ADHD through dysregulation of the right frontostriatal system.

Behavioral effects of excitotoxic lesions of ventral medial prefrontal cortex in the rat are hemisphere-dependent.

The ventral region of the medial prefrontal cortex (mPFC) is highly sensitive to stressful inputs and implicated in a variety of behaviors. Studies have also demonstrated numerous functional hemispheric asymmetries within this brain area of the rat. The present study examines the effects of ibotenic acid or sham lesions targeting the left, right or bilateral infralimbic cortex, on a variety of behaviors. Lesions (which destroyed infralimbic and ventral prelimbic cortex) were without effect on acquisition or reversal of a spatial learning task in the Morris water maze. Similarly unaffected were spontaneous and amphetamine-induced locomotor activity and sensitization, and prepulse inhibition of the acoustic startle response. In contrast, lesions significantly affected behavior in the elevated plus maze, as right-lesioned animals spent more time exploring the open arms of the maze than shams or left-lesioned rats, while not differing in closed arm entries. As well, in a simple taste aversion paradigm, right-lesioned rats drank significantly more of a sweetened milk/quinine solution than shams and left-lesioned rats, despite not differing in consumption of sweetened milk alone. The anxiolytic effects of right, but not left lesions of ventral mPFC, parallel the asymmetrical suppression of physiological stress responses previously reported for similar lesions. It is suggested that the right ventral mPFC plays a primary role in optimizing cautious and adaptive behavior in potentially threatening situations.

Prefrontal cortical regulation of hypothalamic-pituitary-adrenal function in the rat and implications for psychopathology: side matters.

In recent years, dysfunction of hypothalamic-pituitary-adrenal (HPA) axis function has been implicated in a wide variety of psychiatric conditions. The importance of this system in responding to and coping with stress is well documented, and the integrity of such systems is of obvious significance to good mental health. The prefrontal cortex (PFC) is also heavily implicated in numerous psychopathological conditions. There is thus a growing interest in the potential role the PFC might play in regulating HPA function, and whether abnormalities of these systems are linked. The present paper reviews a number of recent animal studies which have attempted to elucidate the role of the PFC in regulation of HPA axis function, and how these systems may interact. It is concluded that the PFC is involved both in activating HPA responses to stress and in the negative feedback regulation of this system. Cerebral laterality is an important feature of this regulation, with the right PFC being most directly linked to stress-regulatory systems. On this basis, a number of parallels are drawn to the human literature, where asymmetrical disturbances in PFC activity may help explain associated patterns of HPA dysfunction.