Dopaminergic Modulation of Adult Neurogenesis in Neurodegenerative Disorders

Adult neurogenesis, the generation and integration of new neurons in the mature brain, is tightly regulated by dopaminergic signalling. Dopamine, acting through D1-like and D2-like receptors, influences proliferation, survival and differentiation of neural progenitors within the subventricular zone and dentate gyrus. In neurodegenerative disorders such as Parkinson’s disease, loss of nigrostriatal dopamine not only underlies motor deficits but also impairs non-motor functions—cognition, mood and olfaction—through disruption of neurogenic processes. Genetic mutations affecting mitochondrial quality control, exemplified by PINK1 loss, further compromise dopaminergic support of progenitor pools. Conversely, interventions ranging from deep brain stimulation and receptor-selective agonists to motor skill training can restore or enhance adult neurogenesis by reactivating key signalling cascades (PKA/CREB, AMPK/BDNF). Understanding the interplay between dopaminergic circuits and neurogenic niches offers promising avenues for regenerative therapies aimed at slowing or reversing neuronal loss across a spectrum of neurodegenerative conditions.

Research from Nature Portfolio

Analyses using complementary model systems have illuminated intrinsic and extrinsic regulators of dopamine-dependent neurogenesis. In PINK1-deficient zebrafish and human organoids, adult generation of dopaminergic neurons declines markedly, implicating mitochondrial dysfunction in early progenitor commitment rather than late differentiation. This discovery pinpoints a vulnerable window for intervention in familial Parkinsonism. In a separate study, motor skill learning via rotarod exercise in a subacute MPTP mouse model activated AMPK and upregulated BDNF, leading to robust increases in newborn neurons across the subventricular zone, dentate gyrus, striatum and substantia nigra. These findings demonstrate that targeted behavioural stimuli can engage dopaminergic pathways to bolster adult neurogenesis and support functional recovery.

Dopaminergic Modulation of Adult Neurogenesis in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in dopaminergic modulation of adult neurogenesis in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Adult neurogenesis: Generation of new neurons from neural stem or progenitor cells in the adult brain.

Subventricular zone (SVZ): A lateral ventricular niche where progenitors produce interneurons for the olfactory bulb.

Subgranular zone (SGZ): A region of the hippocampal dentate gyrus where progenitors give rise to granule neurons.

Dopamine receptors (D1-like, D2-like): G-protein-coupled receptors mediating distinct intracellular signalling; D1-like activate PKA, D2-like modulate alternative cascades.

PINK1: A mitochondrial kinase essential for mitophagy; mutations cause familial Parkinson’s disease and impair progenitor function.

AMPK: Adenosine monophosphate-activated protein kinase, a metabolic sensor that promotes neurogenesis and BDNF expression in response to activity.

BDNF: Brain-derived neurotrophic factor, a neurotrophin critical for survival, differentiation and synaptic plasticity of neurons.

References

1. Subthalamic nucleus but not entopeduncular nucleus deep brain stimulation enhances neurogenesis in the SVZ-olfactory bulb system of Parkinsonian rats. Frontiers in Cellular Neuroscience (2024).
2. MPTP Impairs Dopamine D1 Receptor-Mediated Survival of Newborn Neurons in Ventral Hippocampus to Cause Depressive-Like Behaviors in Adult Mice. Frontiers in Molecular Neuroscience (2016).
3. PINK1 deficiency impairs adult neurogenesis of dopaminergic neurons. Scientific Reports (2021).
4. Neurogenic effects of rotarod walking exercise in subventricular zone, subgranular zone, and substantia nigra in MPTP-induced Parkinson’s disease mice. Scientific Reports (2022).