Hippocampal Regulation of Aggression

Recently, I read a paper entitled “A Circuit From Hippocampal CA2 to Lateral Septum Disinhibits Social Aggression,” published in Nature in December of 2018. Not only is this work of incidental interest to me, as my Neurobiology teaching assistant is a co-author and has discussed its implications with me at length, but the profound questions surrounding the field more broadly are also relevant to my professional ambitions. As an aspiring neurosurgeon and author exploring the intersection between medicine and the human condition, I have an insatiable curiosity about the ways in which our neural physiology, and potential perturbations to its structures, can contribute vitally to a patient’s quality of life and social behavior. Because the CA2 region of the hippocampus, through its role in declarative memory formation, is essential to social identity in humans, I felt an urgent need to learn more about this structure to be mindful of its importance in my future surgical interventions.

The principal investigators of this paper are Drs. Steven Siegelbaum and Eric Kandel. Dr. Siegelbaum is the Chair of the Neuroscience Department at the Jerome Greene Science Center while Dr. Kandel is co-Director of the Zuckerman Institute and recipient of the Nobel Prize in Physiology or Medicine in 2000. Both professors have been active contributors to a growing field of investigation into the electrical and synaptic behavior of neurons in the cortico-hippocampal circuit, as well as how their activity influences learning and memory. Moreover, they have contributed seminal insights to our current understanding of neural plasticity, producing robust findings on the mechanisms underpinning short- and long-term synaptic potentiation. 

In this paper, they set out to answer a critical question puzzling neuroanatomists for years. Prior to their findings, the hippocampus was thought to be important mainly in forming declarative memories of social interactions, but it was less certain how CA2 neurons were associated with motivation regulation structures in the brain, especially those implicated in social aggression. While the field did not know whether and specifically how the hippocampus mediates aggressive behavior, the authors were adamant that an animal’s tendency to be aggressive depends heavily on an evaluation of its own status – based on memories of past social encounters. Consequently, a socially superior animal is more likely to attack an inferior while the reverse is less likely, an intuitive behavioral relationship suggesting that the hippocampus may modulate biological pathways implicated in socially aggressive behaviors.

Using a variety of techniques like immunohistochemistry, whole-cell electrophysiological recordings, CA2 silencing/overexpression, and behavioral paradigms measuring social aggression and memory, the authors convincingly found that hippocampal neurons modulate the activity of the Lateral Septum (LS), which is associated with socially aversive behaviors. Particularly, CA2 stimulation in male and female mice disinhibited a subnucleus of the ventromedial hypothalamus well known to provoke attacks and robustly released arginine vasopressin in the brain. The authors found that these effects either formed a new declarative memory of a social encounter or facilitated aggressive behavior in the mice (i.e. causing them to attack). On the other hand, silencing CA2 neurons reduced both the percentage of mice engaged in aggressive behavior (i.e. bites, attacks, tail rattles), as well as the total duration of each attack. In this way, the authors argued that there is a necessary and sufficient relationship between the hippocampus and motivation regulation structures like the LS. Providing biomolecular, electrophysiological, and behavioral evidence, they indicate that animals can, based on their status and familiarity with a target, consult past memories and then decide whether or not to be aggressive.

The potential societal contributions of this research are immense. At the core, the authors assert that the brain is functionally and behaviorally interconnected; even neural regions noted primarily for their contributions to more specific pathways (such as the hippocampus and declarative memory) can interact in a variety of different neural circuits and even recruit the endocrine system via the hypothalamus. As a whole, the authors urge the field to move away from hyper-specialization and instead be mindful of how particular areas of the brain may interact holistically with a variety of other regions currently thought to be unrelated. This paper, then, not only has scientific value, but it also points to an oncoming cultural evolution in neuroscience research more broadly. 

Ultimately, these findings have inspired in me a myriad of potential research ideas, inciting a newfound passion to study how brain tumors like glioblastoma – known to invade the hippocampus in both hemispheres – can alter declarative memory, aggressive behavior, or personality in terminal patients. At the Bartoli Brain Tumor Laboratory at NewYork-Presbyterian, I hope to develop novel treatments for inoperable, metastatic brain tumors while preserving the behavioral integrity of patients – often a massive hurdle in such complex neurosurgical cases. I have found it extremely enriching to read this paper and understand the interactions of the hippocampus in a range of behaviors. I hope to eventually apply this work towards determining how tumors invading the hippocampus could be safely resected; moreover, it would be fascinating to uncover how the hippocampus mediates other social behaviors like altruism, teamwork, or territorial disputes. Potential extensions of this research, however, will not happen overnight, especially in human models. Instead, they will require the combined intellectual willpower of an entire generation of budding neuroscientists as we aim to further expand our knowledge of the brain. 

References

Leroy, F., Park, J., Asok, A., Brann, D. H., Meira, T., Boyle, L. M., … & Siegelbaum, S. A. (2018). A circuit from hippocampal CA2 to lateral septum disinhibits social aggression. Nature, 564(7735), 213.

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