The Effect And Mechanisms Of Lateral Habenula On Depressive-like B’ehavior In Rats Of Parkinsons Disease

Parkinson’s disease (PD) is a common degenerative disease of the centralnervous system in the elderly. The motor symptoms of PD are widely known and hasbeen the focus of attention of many researchers. However, we should not neglect themood disorders showed in most PD patients, such as depression because theyseriously affect the quality of life and prognosis of PD patients, and even become adirect cause of death in these patients. Recently，mood disorders associated with PDhave begun to attract attention, however their pathogenesis remains unclear.Movement disorders result from reductions in dopamine levels in the striatum,which are caused by degenerative pathological changes in midbrain substantia nigrapars compacta dopaminergic neurons. Thus, degeneration of substantia nigradopaminergic neurons is an important cause of Parkinson’s disease (PD),PD is associated with not only degenerative changes in dopaminergic neuronsin the substantia nigra but also changes in serotonergic neurons in the raphe nucleus.Abnormalities in the central5-hydroxytryptamine (5-HT) neurotransmission arethought to play a key role in the pathogenesis of depression. It is widely known thata decreased5-HT level in the raphe nucleus is related to the onset of depression.Interestingly, Mayeux et al. have shown that5-hydroxyindoleacetic acid levels in thecerebrospinal fluid of PD patients with depression were less than those of normalcontrols and nondepressed PD patients. In addition, serotonin reuptake inhibitors canmarkedly improve depressive-like symptoms in PD patients. Consequently,depression symptoms in PD patients may be the result of the interaction of the twosystems. The lateral habenula (LHb) is closely related to the substantia nigra and raphenucleus, and it plays an important role in the pathogenesis of depression. The lateralhabenula is an epithalamic region that directly projects into the substantia nigra andraphe nucleus, and plays a role in regulating physiological functions, for examplemood and sleep. In recent years, increasing attention has been paid to the role ofLHb in depression. In depressed animals and patients, LHb activity is enhanced.Moreover, high-frequency electrical stimulation of the habenula can alleviatedepressive symptoms that cannot be improved by antidepressants Additionally, inanimal models, LHb lesions can improve depressive-like behavior by increasingraphe5-HT levels. To date, the relationships between the LHb and substantia nigradopaminergic neurons have been of widespread concern, Lesions of the substantianigra pars compacta (SNC) and ventral tegmental area (VTA) can increase LHbglucose use rates. Therefore, the LHb not only directly controls substantia-nigra andraphe-nucleus activities, but it also acts as a bridge for communication between thesubstantia nigra dopamine system and the raphe nucleus serotonin system.Accordingly, we hypothesized that substantia nigra dopaminergic neuron lossesin PD rats would reverse LHb inhibitory activities, which would in turn increaseLHb suppression on the raphe neurons and decrease5-HT levels in the raphenucleus.In this study, we applied behavioral, electrophysiological and neurobiochemistr-y methods to prove the role of the lateral habenula in the pathogenesis of Parkinso-n’s disease with depression and then to prove that the lesion effect of the lateralhabenula is related to the improvement of depressive-like behavior in Parkinson’sdisease model ratsThe results showed that（1）In the forced swim test, we screened PD rats for depressive-like behaviors(PDD). we found that LHb lesions decreased depressive-like behavior as indexed bydecreased immobility times and increased climbing times. Meanwhile, LHb lesionsenhanced5-HT levels in the raphe nucleus as measured by high-performance liquid chromatography.（2）We found that the cytochrome c oxidase activity in the LHb of PDD rats wastwice that of control rats. The results of18F-2DG percentage of injected dose pergram showed that8F-2DG percentage of injected dose per gram were increasedsignificantly in the LHb of PDD rats.（3）The results of extracelluar firing in vivo showed that after injection ofapomorphine that was a kind of dopamine agonist the spontaneous firing rates of65.9%neurons in the lateral habenula were significantly decreased,18.3%neuronshad no significant changes and15.9%neurons were increased; after intraperitonealinjection of haloperidol that was a kind of dopamine antagonist the spontaneousfiring rates of neurons in the lateral habenula had no significant changes. The duringof injection apomorphine associated by injection of haloperidol, Theapomorphine-mediated suppression is blocked by intraperitoneal injection ofhaloperidol.Therefore, we observed the effect of LHb lesions on depressive-like behaviorand5-HT concentration of raphe nuclei in PD rats to testify the LHb-raphe nucleipathway related to pathogenesis of depression associated with PD. Theseresults suggest that LHb lesions improve depressive-like behavior in PD rats byincreasing5-HT levels in the raphe nucleus. Thus, in the pathogenesis of PD in ratswith depressive-like behavior, the LHb appears to mediate the effects ofdopaminergic neurons in the substantia nigra on serotonergic neurons in the raphenucleus. These results provide an evidence to reveal that the lateral habenula closelycorrelates with PD with depression.