Research
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Exploring behavioral and neuronal plasticity within circuits that generate social behaviors
Social interactions are vital for well-being, social cohesion, and societal progress. Disruptions in social information processing can have devastating consequences for both the individual and the people in their life. My studies focus on how animals process complex external and internal cues to seamlessly navigate in distinct social settings. To do this, my research focuses on sex hormone-responsive neural circuits that generate social behaviors in mice. Sex hormones (e.g., testosterone, estradiol, progesterone) profoundly shape neural architecture and function, including circuits that generate sexually differentiated social behaviors(1,2). Therefore, I use cell type-specific genetic access and innovative methods of neural imaging, manipulation, and circuit mapping in mice to dissect the role of sex hormone-responsive neural pathways in the generation of fundamental elements of social behaviors. My work aims to understand how the social brain functions in health and how some individuals are resilient to detrimental changes in these circuits following adverse social experiences, which may ultimately help guide future therapies for symptoms of altered social behaviors in neurological conditions, especially those that exhibit sex differences.
Biological sex profoundly shapes neurobiology
In mammals, presence or absence of a single gene (SRY) on the male-specific Y chromosome starts a cascade of events resulting in markedly different sex hormone levels in males and females(3-5). Sex hormones profoundly shape the development and function of the brain with effects so potent that naturally occurring mutations that alter their signaling can override genetic sex(6-7). For example, XX humans with congenital adrenal hyperplasia who experience elevated levels of perinatal testosterone exhibit increased male-typical social behaviors(6), and XY humans with a null mutation for androgen receptor display female-typical social behaviors(7).
Sex hormone receptors and enzymes are expressed in discrete neural populations throughout the brain, and sex hormones acting via these receptors can cause long-lasting and acute changes in these neurons.
Thus, the degree of brain masculinization/feminization is determined by both titer and class of circulating sex hormones as well as expression levels of the receptors and enzymes in individual regions. Together, these factors create in each individual a feminine-masculine spectrum of gene expression, neural circuit wiring, neural activity, and ultimately, behavior. How individual variability in the development of sexually differentiated neural circuits and behaviors can manifest in distinct ways in individual animals is a question I plan to explore in future research.
Current Research
Because sex hormones powerfully modulate social behaviors in mammals, the neural circuits that regulate these behaviors must be sex hormone responsive (e.g., express sex hormone receptors), which provides insight into the identity of the specific neurons that regulate these social behaviors. Sex hormone receptors are expressed throughout the brain in specific regions where they constitute subsets of cells intermingled with non-sex hormone responsive cells. Such intermingling of these cells with other cell types has made it challenging to characterize their roles in behavior. Thus, I utilize cell type-specific genetic access and innovative methods of neural imaging and manipulation in mice to dissect the role of sex hormone responsive neural circuits in the encoding and generation of fundamental aspects of social behavior(8).
I recently used this approach to functionally characterize a sex hormone responsive subset of neurons in a brain region known to be sexually differentiated and implicated in social behaviors in many vertebrates, including mice and humans(9-12). These experiments in mice led to the identification of, for the first time in the vertebrate brain, a neural locus for innate conspecific sex/mate recognition(13).
Cell number in the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr) is typically greater in males compared to females(9-12).
Neurons expressing aromatase (red above), an enzyme essential for estradiol synthesis, label a subset of BNSTpr neurons. Genetic access to this population enabled isolated imaging and manipulation of their neural activity during social interactions.
In males but not females, these BNSTpr neurons are more active during social interactions with females compared to males.
Inhibition of this activity impedes the ability to distinguish females and males and disrupts all subsequent social displays.
Amazingly, transient activation mimicking the natural activity of these neurons during interaction with a female is sufficient to reduce aggression and promote mating toward males.
BNSTpr activity-induced male-male mating is not time-locked to activation but begins when mating is typically initiated toward females, indicating that this node of the neural circuit encodes sex/mate recognition and does not directly drive motor output. That is, male BNSTpr activity encodes the perception of another conspecific as a potential mate.
In unpublished studies, I have linked this neural locus all the way upstream to olfactory input in the nose and downstream to mating motor command neurons. Moreover, I discovered a highly sexually differentiated projection (~8x stronger in males vs females) to the medial preoptic area (mPOA) that is masculinized by testosterone (T) treatment.
I have also uncovered a neuropeptidergic mechanism that underlies the downstream communication of this sex/mate recognition signal to mating motor command neurons. I plan to publish these exciting data very soon.
Brain regions implicated in social behaviors are highly conserved across mammals. For example, the BNSTpr is also sexually differentiated in humans and implicated in social behaviors(10-12). Therefore, these studies using mice as research models provide fundamental insights into how social information is encoded and processed in the mammalian brain.
Future Directions
I have a genetic handle on direct inputs into this sexually differentiated social information processing circuit from the ventral hippocampus (vHPC), nucleus accumbens (NAc), and ventral tegmental area (VTA). The vHPC is implicated in emotional processing and the storage of social memories(14), which evokes the exciting possibility of a convergence between sex/mate recognition and social memory. The NAc and VTA are implicated in neural processing of rewards and motivation(15). Therefore, inputs from these neural loci may provide information about the reward/valence associated with social interactions. In my own lab, I plan to functionally characterize these potential social memory and reward inputs into this circuit both in health as well as in mouse models of substance abuse and neurological conditions, such as Alzheimer’s Disease and autism spectrum disorders. In addition, my future research program will include studies that get to the heart of how individual variability in the development of sexually differentiated neural circuits and behaviors can manifest in distinct ways in individual animals, which has important implications for human biology.
References
1. Yang CF, Shah NM. Representing sex in the brain, one module at a time (2014) Neuron 82:261–278.
2. Wu MV, Shah NM. Control of masculinization of the brain and behavior (2011) Curr Opin Neurobiol., 21(1):116-23.
3. Morris, JA, Jordan, CL, Breedlove, SM. Sexual differentiation of the vertebrate nervous system (2004) Nat Neurosci., 7:1034-1039.
4. Arnold AP. The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues (2009) Horm Behav., 55(5):570-8.
5. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade (1995) Cell, 83:835–839.
6. Zucker KJ, Bradley SJ, Oliver G, Blake J, Fleming S, Hood J. Psychosexual development of women with congenital adrenal hyperplasia (1996) Hormones and Behavior, 30:300-318.
7. Bramble MS, Lipson A, Vashist N, Vilain E. Effects of chromosomal sex and hormonal influences on shaping sex differences in brain and behavior: Lessons from cases of disorders of sex development (2017) J. Neuro Res 95:65-74.
8. Bayless DW, Shah NM. Genetic dissection of neural circuits underlying sexually dimorphic social behaviours (2016) Phil. Trans. R. Soc. B, 371:20150109.
9. Wu, MV, Manoli, DS, Fraser, EJ, Coats, JK, Tollkuhn, J, Honda, SI, Harada, N, Shah, NM. Estrogen masculinizes neural pathways and sex-specific behaviors (2009) Cell, 139:61–72.
10. Chung WCJ, De Vries GJ, Swaab D. Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood (2002) J Neuro., 22(3):1027–1033
11. Zhou JN, Hofman MA, Gooren LJ, Swaab DF. A sex difference in the human brain and its relation to transsexuality (1995) Nature, 378(6552):68-70.
12. Kruijver FPM, Zhou JN, Pool CW, Hofman MA, Gooren LJG, Swaab DF. Male-to-female transsexuals have female neuron numbers in a limbic nucleus (2020) J. Clinical Endocrin & Metabol, 85(5):2034-2041.
13. Bayless DW, Mason MM, Susanto AT, Lobdell A, Shah NM. Limbic neurons shape sex recognition and social behaviors in sexually naïve males (2019) Cell, 176:1190-1205.
14. Okuyama T,Kitamura T, Roy DS, Itohara S, Tonegawa S. Ventral CA1 neurons store social memory. (2016) Science, 353: 1536-15.
15. Knowland D, Lim BK. Circuit-based frameworks of depressive behaviors: The role of reward circuitry and beyond (2018) Pharmacol Biochem Behav, 174:42-52.
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