Abstract
BackgroundThe habenula plays an important role on cognitive and affective functions by regulating monoamines transmission such as the dopamine and serotonin, such that its dysfunction is thought to underlie a number of psychiatric conditions. Given that the monoamine systems are highly vulnerable to neurodevelopmental insults, damages in the habenula during early neurodevelopment may cause devastating effects on the wide-spread brain areas targeted by monoamine innervations.Methodology/Principal FindingsUsing a battery of behavioral, anatomical, and biochemical assays, we examined the impacts of neonatal damage in the habenula on neurodevelopmental sequelae of the prefrontal cortex (PFC) and nucleus accumbens (NAcc) and associated behavioral deficits in rodents. Neonatal lesion of the medial and lateral habenula by ibotenic acid produced an assortment of behavioral manifestations consisting of hyper-locomotion, impulsivity, and attention deficit, with hyper-locomotion and impulsivity being observed only in the juvenile period, whereas attention deficit was sustained up until adulthood. Moreover, these behavioral alterations were also improved by amphetamine. Our study further revealed that impulsivity and attention deficit were associated with disruption of PFC volume and dopamine (DA) receptor expression, respectively. In contrast, hyper-locomotion was associated with decreased DA transporter expression in the NAcc. We also found that neonatal administration of nicotine into the habenula of neonatal brains produced selective lesion of the medial habenula. Behavioral deficits with neonatal nicotine administration were similar to those caused by ibotenic acid lesion of both medial and lateral habenula during the juvenile period, whereas they were different in adulthood.Conclusions/SignificanceBecause of similarity between behavioral and brain alterations caused by neonatal insults in the habenula and the symptoms and suggested neuropathology in attention deficit/hyperactivity disorder (ADHD), these results suggest that neurodevelopmental deficits in the habenula and the consequent cortico-striatal dysfunctions may be involved in the pathogenesis and pathophysiology of ADHD.
Highlights
The habenula is a part of the dorsal diencephalic conduction system, comprising of two distinct nuclei, the medial (MHb) and lateral (LHb) habenula [1]
We have shown that neonatal habenula lesion (NHL) induces neurodevelopmental sequelae of the cortico-striatal functions, which induces behavioral alterations resembling to the symptoms of attention deficit/hyperactivity disorder (ADHD)
DA D3 receptor and DA receptor and transporter (DAT) expressions were decreased in the prefrontal cortex (PFC) and nucleus accumbens (NAcc), respectively, of juvenile, but not adult, NHL rats
Summary
The habenula is a part of the dorsal diencephalic conduction system, comprising of two distinct nuclei, the medial (MHb) and lateral (LHb) habenula [1]. The MHb receives inputs mainly from the limbic system, and sends outputs to the interpeduncular nucleus [1], which in turn regulates activity of monoamine, such as dopamine (DA) and serotonin (5HT), neurons located in the ventral tegmetnal area/substantia nigra pars compacta and dorsal raphe, respectively [1]. Because of the neural network organizations of the habenula as the intersection between the limbic system and monoamine neurons in the midbrain, the habenula plays a critical role on regulation of monoamine transmission in widespread brain areas including the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Given that the monoamine systems are highly vulnerable to neurodevelopmental insults, damages in the habenula during early neurodevelopment may cause devastating effects on the wide-spread brain areas targeted by monoamine innervations
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