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Novel insights into minipuberty and GnRH: Implications on neurodevelopment, cognition, and COVID-19 therapeutics
Konstantina Chachlaki1,2, Kevin Le Duc2,3, Laurent Storme2,3
1Univ. Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR_S1172, Lille, France.
Insights
Minipuberty, a neonatal surge in gonadotropin-releasing hormone (GnRH), impacts brain development beyond reproduction. Deficiencies are linked to cognitive and sensory deficits, suggesting therapeutic potential for neurodevelopmental disorders.
Area of Science:
- Neuroendocrinology
- Developmental Neuroscience
- Reproductive Biology
Background:
- The first 1000 days of life are critical for human brain development.
- Minipuberty, a postnatal surge in gonadotropin-releasing hormone (GnRH) neuron activity, is crucial for hypothalamic-pituitary-gonadal (HPG) axis development and reproductive function.
- Emerging evidence suggests minipuberty's influence extends to sensory and cognitive maturation.
Purpose of the Study:
- To review recent findings on the extended role of minipuberty in neurodevelopment.
- To explore the impact of GnRH neuron activity on cognitive and sensory functions.
- To discuss potential therapeutic interventions for neurodevelopmental and cognitive disorders.
Main Methods:
- Review of recent studies on minipuberty, GnRH neuron function, and neurodevelopment.
- Analysis of mouse models investigating nitric oxide (NO) and GnRH deficiency.
- Examination of Down syndrome models and COVID-19's impact on GnRH production.
Main Results:
- Nitric oxide (NO) deficiency is linked to impaired minipuberty, cognitive, and olfactory deficits in mice.
- Age-dependent decline in GnRH production, traceable to minipuberty, is associated with adult cognitive and sensory defects in a Down syndrome mouse model.
- GnRH neurons are susceptible to SARS-CoV-2, raising concerns about potential long-term neurodevelopmental consequences.
Conclusions:
- GnRH neurons play an unexpected role in sensory and cognitive development, in addition to reproduction.
- Therapeutic strategies like inhaled NO in infancy and pulsatile GnRH in adults show promise for treating neurodevelopmental and cognitive disorders.
- Understanding the interplay between GnRH, HPG axis, and brain circuits is vital for addressing cognitive aging and developmental disorders.
Abstract:
In humans, the first 1000 days of life are pivotal for brain and organism development. Shortly after birth, gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus are activated, a phenomenon known as minipuberty. This phenomenon, observed in all mammals studied, influences the postnatal development of the hypothalamic-pituitary-gonadal (HPG) axis and reproductive function. This review will put into perspective the results of recent studies showing that the impact of minipuberty extends beyond reproductive function, influencing sensory and cognitive maturation. Studies in mice have revealed the role of nitric oxide (NO) in regulating minipuberty amplitude, with NO deficiency linked to cognitive and olfactory deficits. Additionally, findings indicate that cognitive and sensory defects in adulthood in a mouse model of Down syndrome are associated with an age-dependent decline of GnRH production, whose origin can be traced back to minipuberty, and point to the potential therapeutic role of pulsatile GnRH administration in cognitive disorders. Furthermore, this review delves into the repercussions of COVID-19 on GnRH production, emphasizing potential consequences for neurodevelopment and cognitive function in infected individuals. Notably, GnRH neurons appear susceptible to SARS-CoV-2 infection, raising concerns about potential long-term effects on brain development and function. In conclusion, the intricate interplay between GnRH neurons, GnRH release, and the activity of various extrahypothalamic brain circuits reveals an unexpected role for these neuroendocrine neurons in the development and maintenance of sensory and cognitive functions, supplementing their established function in reproduction. Therapeutic interventions targeting the HPG axis, such as inhaled NO therapy in infancy and pulsatile GnRH administration in adults, emerge as promising approaches for addressing neurodevelopmental cognitive disorders and pathological aging.
