2026 ECNP Congress

EP02-2086

The regulation of social behaviour by the medial prefrontal cortical neurons projecting to the medial preoptic area

Luca Darai — T.C. Kállai, D. Keller, M. Cservenák, Á. Dobolyi · Eötvös Loránd University, Laboratory of Molecular and Systems Neurobiology- Department of Physiology and Neurobiology, Budapest, Hungary

2026 ECNP Congress

The medial prefrontal cortex (mPFC) plays a pivotal role in the regulation of social behaviour, and its dysfunction has been implicated in several neuropsychiatric disorders, including autism spectrum disorder and schizophrenia. Additionally, the mPFC is responsible for motivational and emotional regulation, however, it is important to note that these brain functions are not solely governed by the mPFC, other cortical and subcortical structures are also involved in the regulations [1]. The mPFC exerts its influence through distinct projection neuron populations characterized by their target regions, such as cortico-cortical, cortico-thalamic, and subcortical pathways [2]. Despite increasing knowledge about these circuits, the subtype-specific contribution of defined projection neurons to different components of social behaviour remains insufficiently understood. In the present study, we aimed to map the projection patterns of mPFC neurons targeting the medial preoptic area (MPOA), a major hub of the control of social behaviors, to investigate their functional contribution to social behavior with chemogenetics tools.

To achieve pathway-specific control, stimulatory and inhibitory designer receptors were selectively expressed via viral gene transfer in mPFC neurons projecting to the MPOA. The mPFC neurons projecting to the MPOA gave rise to collaterals to several subcortical areas, such as the nucleus accumbens, ventral pallidum, lateral septum, paraventricular and ventromedial hypothalamic nuclei, as well as the medial amygdala, while notably lacking projections to the thalamus. To examine the location of cortico-preoptic neurons and comparison with the cortico-thalamic neurons, double retrograde tracing further demonstrated a laminar segregation, with MPOA-projecting neurons primarily located in layer V and thalamus-projecting neurons in layer VI, suggesting distinct developmental and functional identities.

Functional assessment using chemogenetic approaches revealed distinct roles for these projection systems. Activation of cortico-preoptic mPFC neurons resulted in reduced sociability in the three-chamber sociability test, although direct social interactions between freely moving animals remained largely unaffected. Conversely, inhibition of these neurons did not alter overall sociability but increased the duration of specific behavioural elements, indicating a essential modulatory role in shaping interaction dynamics. When manipulation was restricted to the MPOA via local CNO (ligand) administration, stimulation selectively reduced chasing behaviour without affecting sociability, whereas inhibition enhanced both chasing and mounting behaviours. These findings point to a dissociation between general social preference and specific social action patterns, and suggest a context-dependent and projection-specific modulation of behavioural outputs.

Overall, our results demonstrate that mPFC neurons projecting to the MPOA can have a differential regulatory effect on social behaviours based on the collateral contributions. The observed differences between global and projection-specific manipulations highlight the importance of collateral projections and circuit-level organization in shaping behavioural outcomes. The cortico-preoptic pathway does not underlie basic social motivation but rather modulates behavioural outputs in a context-dependent way. This functional specialization advances our understanding of the neural circuitry underlying social behaviour and may provide a framework for developing targeted therapeutic approaches for social aspects of neuropsychiatric disorders.

Grant support: EKÖP-25 University Excellence Scholarship Program of the Ministry for Culture and Innovation, Richter Gedeon Centenary Foundation Talentum Scholarship 2025, NAP3 (NAP2022-I-3/2022), NKFIH OTKA K146077

References

  1. : Arnsten, A.F., and Rubia, K. (2012). Neurobiological circuits regulating attention, cognitive control, motivation, and emotion: disruptions in neurodevelopmental psychiatric disorders. J Am Acad Child Adolesc Psychiatry 51, 356-367.
  2. : Anastasiades, P.G., and Carter, A.G. (2021). Circuit organization of the rodent medial prefrontal cortex. Trends Neurosci 44, 550-563.