Investigating affective neuropsychiatric symptoms in rodent models of Parkinson's disease.

Affective neuropsychiatric disorders such as depression, anxiety and apathy are among the most frequent non-motor symptoms observed in people with Parkinson's disease (PD). These conditions often emerge during the prodromal phase of the disease and are generally considered to result from neurodegenerative processes in meso-corticolimbic structures, occurring in parallel to the loss of nigrostriatal dopaminergic neurons. Depression, anxiety, and apathy are often treated with conventional medications, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and dopaminergic agonists. The ability of these pharmacological interventions to consistently counteract such neuropsychiatric symptoms in PD is still relatively limited and the development of reliable experimental models represents an important tool to identify more effective treatments. This chapter provides information on rodent models of PD utilized to study these affective neuropsychiatric symptoms. Neurotoxin-based and genetic models are discussed, together with the main behavioral tests utilized to identify depression- and anxiety-like behaviors, anhedonia, and apathy. The ability of various therapeutic approaches to counteract the symptoms observed in the various models is also reviewed.

Serotonergic and dopaminergic neurons in the dorsal raphe are differentially altered in a mouse model for parkinsonism.

Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline (NA) reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both NA and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.

Maternal Aggression Driven by the Transient Mobilisation of a Dormant Hormone-Sensitive Circuit.

Aggression, a sexually dimorphic behaviour, is prevalent in males and typically absent in virgin females. Following parturition, however, the transient expression of aggression in adult female mice protects pups from predators and infanticide by male conspecifics. While maternal hormones are known to elicit nursing, their potential role in maternal aggression remains elusive. Here, we show in mice that a molecularly defined subset of ventral premammillary (PMvDAT) neurons, instrumental for intermale aggression, switch from quiescence to a hyperexcitable state during lactation. We identify that the maternal hormones prolactin and oxytocin excite these cells through actions that include T-type Ca2+ channels. Optogenetic manipulation or genetic ablation of PMvDAT neurons profoundly affects maternal aggression, while activation of these neurons impairs the expression of non-aggression-related maternal behaviours. This work identifies a monomorphic neural substrate that can incorporate hormonal cues to enable the transient expression of a dormant behavioural program in lactating females.