The research team led by Prof. Han Xu has recently published an article titled ‘The basal forebrain to lateral habenula circuitry mediates social behavioral maladaptation’ on Nature Communications online on May 13, 2024. This research discovered a novel neural circuit mechanism of glutamatergic neurons in the basal forebrain (BF) mediating social behavioral maladaptation through their projection to the lateral habenula (LHb).

In our daily life, we spend around 80% of our waking time in social related activities. A good social environment is not only indispensable for our personal survival and reproduction as well as the harmony and stability of our society, but also it provides us with the positive emotional value, which is essential for maintaining our mental health. Unfortunately, social dysfunctions are common in many neuropsychiatric disorders, including autism, depression, and social phobia. Avoidance and fearful responses to social stimuli are typical behavioral symptoms of social phobia, which seriously affects patients' physical, mental health and social functions. Adverse social experiences are important factors for the development of social fear; however, it is still unclear how these negative social experiences act on brain function and eventually lead to social fear behaviors.

The basal forebrain (BF), located in the rostroventral forebrain and is well-known for its enrichment with cholinergic projection neurons, while little is known about the functions of the other two main types of neurons within the BF (GABAergic and glutamatergic neurons). A prior report by the team in 2021 revealed for the first time that a subpopulation of SST-expressing GABAergic neurons in the BF could modulate pro-social behaviors [1], suggesting that the different types of neurons within the BF may be specific in the modulation of behaviors. Interestingly, a human brain imaging study showed a significant increase in BF activity in patients with PTSD while processing trauma-related words [2]. Similarly, a recent report also found that individuals with more severe levels of social anxiety showed abnormal activation of the BF, suggesting that the BF is involved in the processing of negative emotions [3]. However, whether and how the BF is directly contributed to social fear behavior remains an important but unresolved question.

The research team first induced stable and intense social fear behavior in mice using conditioned social fear conditioning. In vivo multichannel electrophysiology and fiber photometry revealed that a large number of vGluT2-expressing glutamatergic neurons in the BF were activated during social fear expression, whereas cholinergic and GABAergic neurons showed no significant changes in their activity. Using neuron type-specific manipulation approaches, they found that inhibition of vGluT2 neurons dramatically attenuated social fear behavior but not cholinergic or GABAergic neurons, suggesting that BF glutamatergic neurons plays an essential role in the expression of social fear.

Through what downstream targets do BF vGluT2 neurons mediate social fear? The research team first used viral tracing and brain slice patch clamp recordings to reveal that vGluT2 neurons have close anatomical connectivity and monosynaptic functional links with both the ventral tegmental area (VTA) and lateral habenula (LHb). Interestingly, BF vGluT2→LHb projections were selectively activated during social fear behaviors, and specific inhibition of the BF vGluT2→LHb projection significantly reduced social fear in mice, while inhibition of BF vGluT2→VTA projections did not alter social fear behaviors. Finally, using brain slice patch clamp techniques, they found that social fear conditioning enhanced the glutamatergic synaptic connections from BF to LHb that may serve as a potential synaptic mechanism underlying social fear modulation by this neural circuit.

Schematic illustration of neural circuit mechanism underlying social fear

This study proposes a novel mechanism of social fear expression that centered on the BF at circuit and cellular levels, which sheds light on our understanding of the neural basis of social anxiety disorders, and may provide new targets for the treatment of social fear related neuropsychiatric disorders in the future.

References

1. Wang, J., et al. Basal forebrain mediates prosocial behavior via disinhibition of midbrain dopamine neurons. Proceedings of the National Academy of Sciences of the United States of America 118 (2021). doi: 10.1073/pnas.2019295118.

2. Rabellino, D., Densmore, M., Frewen, P.A., Theberge, J. & Lanius, R.A. The innate alarm circuit in post-traumatic stress disorder: Conscious and subconscious processing of fear- and trauma-related cues. Psychiatry Res Neuroimaging 248, 142-150 (2016).

3. Zhu, X., et al. Functional Connectivity Between Basal Forebrain and Superficial Amygdala Negatively Correlates with Social Fearfulness. Neuroscience 510, 72-81 (2023).