Essentials: The Biology of Aggression, Mating & Arousal | Dr. David Anderson
Quick Read
Summary
Takeaways
- ❖Internal states, like emotion, arousal, and motivation, are neurobiological processes that alter the brain's input-to-output transformation, distinct from subjective feelings.
- ❖Offensive aggression in male mice is rewarding and is driven by specific neurons in the ventromedial hypothalamus (VMH), which are sensitive to estrogen.
- ❖Social isolation significantly upregulates tachykinin 2 in the brain, leading to increased aggression, fear, and anxiety, effects that can be blocked by the drug osanotonant.
Insights
1Emotion vs. Internal State
Emotions are a class of internal states that control behavior, distinct from subjective feelings. States like arousal, motivation, and sleep change the brain's input-to-output transformation, persisting beyond the initial stimulus and generalizing to new situations.
Dr. Anderson explains that emotions are a type of internal state, like arousal or motivation, that change the brain's input-to-output transformation. He notes that emotions tend to outlast the stimuli that evoke them and can generalize to different situations.
2Neural Circuits for Aggression
The ventromedial hypothalamus (VMH) contains specific neurons that, when activated optogenetically, evoke offensive aggression in mice. This aggression is rewarding to male mice, who will learn to self-stimulate to fight subordinate males.
Work by Dau Lin in Dr. Anderson's lab found that activating specific neurons in the ventromedial hypothalamus (VMH) using optogenetics evokes offensive aggression in mice. This type of fighting is rewarding, as male mice will perform actions to gain the opportunity to beat up a subordinate male.
3Fear Inhibits Offensive Aggression
Neurons generating fear are located in close proximity to offensive aggression neurons in the VMH. Stimulating these fear neurons immediately stops ongoing fights, indicating that fear is hierarchically dominant over offensive aggression.
Dr. Anderson describes the VMH as a pear-shaped structure where aggression neurons are in the lower part and fear neurons in the upper part. He states that strong fear shuts down offensive aggression, and stimulating fear neurons during a fight immediately stops it, causing animals to freeze.
4Estrogen's Role in Male Aggression
The aggression-controlling neurons in the male mouse VMH express the estrogen receptor. Testosterone's effects on aggression are often mediated by its conversion to estrogen via aromatization, demonstrating that estrogen, not just testosterone, is critical for male aggression.
Dr. Anderson's lab identified that aggression-controlling neurons in the VMH express the estrogen receptor. He notes that castrated mice, losing the ability to fight, can have their aggression restored with an estrogen implant, bypassing the need for testosterone, because testosterone is converted to estrogen by aromatase.
5Sex-Specific Aggression and Mating Circuits
Female mice exhibit hyper-aggression only when nursing pups, a behavior that disappears after weaning. Within the female VMH, distinct subsets of estrogen receptor neurons control either fighting or mating, with mating cells being female-specific.
Dr. Anderson explains that female mice only fight when nurturing pups, becoming hyperaggressive during this window. His student, Mongu Leu, showed that within the female VMH, two divisible subsets of estrogen receptor neurons control fighting and mating, with mating cells being female-specific.
6Crosstalk Between Mating and Aggression Circuits
The VMH contains neurons activated during male-female mating. Separately, the medial preoptic area (MPOA) has 'make love, not war' neurons; activating these in a fighting male mouse causes it to stop fighting and attempt to mate. Dense interconnections between VMH and MPOA suggest complex cooperative and antagonistic interactions.
Dr. Anderson notes that a subset of VMHVL neurons are activated during male-female mating. He describes neurons in the medial preoptic area (MPOA) that, when activated in a fighting male, cause it to stop fighting and try to mount the other male. Dense interconnections between VMH and MPOA suggest a balance of cooperative and antagonistic interactions.
7Periaqueductal Gray (PAG) and Pain Modulation
The PAG acts as a 'telephone switchboard' for innate behaviors, with different sectors linked to specific actions. It is implicated in fear-induced analgesia, a phenomenon where pain responses are suppressed during high-fear states (e.g., fighting), potentially mediated by endogenous analgesic peptides from the adrenal gland.
Dr. Anderson describes the PAG as a 'telephone switchboard' where various innate behaviors are implicated. He discusses 'fear-induced analgesia,' where pain is suppressed during high-fear states, citing the example of not feeling pain during a fight but feeling it afterwards, and mentions an adrenal peptide with analgesic activities.
8Tachykinin and Social Isolation
Social isolation increases aggressiveness, fear, and anxiety in flies and mice by upregulating tachykinin 2 in the brain. A drug called osanotonant, which blocks the tachykinin receptor, can reverse all these effects, allowing previously aggressive, isolated mice to peacefully rejoin their groups.
Dr. Anderson's lab found that social isolation increases tachykinin levels in flies and mice, leading to increased aggression, fear, and anxiety. Moriel Zelikovsky's work showed that osanotonant, a tachykinin receptor blocker, reverses these effects, allowing isolated, aggressive mice to be returned to their littermates without attacking them.
9Brain-Body Communication in Emotion
Subjective feelings of emotion are linked to physiological sensations (somatic markers), reflecting bidirectional communication between the brain and body via the peripheral nervous system (sympathetic/parasympathetic) and the vagus nerve. This communication influences heart rate, blood pressure, and gut contractions, feeding back to the brain.
Dr. Anderson discusses Antonio Damasio's somatic marker hypothesis, where subjective feelings are associated with bodily sensations. He explains that brain states activate sympathetic and parasympathetic neurons, affecting organs like the heart and gut, and this information feeds back to the brain via sensory systems, including the vagus nerve.
Bottom Line
The discovery of osanotonant's profound effect on social isolation-induced aggression, fear, and anxiety presents a significant, yet unpursued, opportunity for pharmaceutical companies to test this drug in humans experiencing social isolation stress or bereavement.
This drug, with a good safety profile in humans, could offer a novel therapeutic approach for mental health conditions exacerbated by social isolation, potentially improving outcomes for individuals suffering from severe loneliness, grief, or post-traumatic stress.
Advocate for or fund clinical trials to repurpose osanotonant for human conditions involving social isolation stress, bereavement, or other forms of severe social deprivation, potentially creating a new market for psychiatric medication.
The close proximity and potential 'crossed wires' between aggression and mating circuits in the brain raise a speculative but important question about whether some individuals who engage in sexual violence might have dysfunctional integration of these states, making aggressive sexual acts more rewarding.
This hypothesis suggests a potential neurobiological basis for certain extreme behaviors, opening avenues for research into the neural mechanisms underlying sexual violence and potentially informing future interventions or understanding of these complex pathologies.
Conduct further research into the precise wiring and functional interactions between aggression and mating circuits in the human brain, particularly in individuals with a history of sexual violence, to identify potential biomarkers or therapeutic targets.
Opportunities
Repurposing Osanotonant for Social Stress
Develop and market osanotonant (or similar tachykinin receptor blockers) for human use to mitigate the behavioral and emotional consequences of social isolation, bereavement, or other forms of severe social stress, given its proven efficacy in animal models and good safety profile in prior human trials.
Key Concepts
Emotion as an Iceberg
Dr. Anderson frames emotion as an iceberg, where subjective feeling is the 'tip' (conscious experience), and the 'below the surface' part represents the underlying neurobiological processes and internal states that control behavior.
Brain as a Thermostat (Homeostatic Behaviors)
Homeostatic behaviors (like hunger, thirst) are explained by a 'thermostat model' where the brain maintains a set point, and deviations build up 'hydraulic pressure' (neural activity) until the need is met, driving specific actions.
Lessons
- Recognize that emotions are deeply rooted in neurobiological states, influencing behavior beyond conscious feeling, and consider the underlying physiological processes.
- Understand that social isolation can profoundly alter brain chemistry (e.g., tachykinin upregulation), leading to increased aggression and anxiety, emphasizing the importance of social connection.
- Advocate for further research and development into pharmacological interventions targeting specific neuropeptide systems (like tachykinin) to manage severe behavioral issues linked to social stress, especially for conditions like bereavement or prolonged isolation.
Quotes
"I see emotions as a type of internal state in the sense that arousal is also a type of internal state. Motivation is a type of internal state. Sleep is a type of internal state. They change the input to output transformation of the brain."
"If you think of an iceberg it's the part of the iceberg that's below the surface of the water. The feeling part is the tip."
"If you give those drugs to a socially isolated mouse, it blocks all of the effects of social isolation. It blocks the aggression. It blocks the increased fear and the increased anxiety. And that Moriel described it. The mice just look chill."
"We've got to figure out how emotion systems are controlled in a causal way uh if we ever want to improve on the psychiatric treatments that we have now."
Q&A
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