Essentials: The Biology of Aggression, Mating & Arousal | Dr. David Anderson

1. Emotions are states, not just feelings. It's more useful to treat emotion as a neurobiological internal state (like arousal, motivation, or sleep) that changes how the brain transforms input into output, rather than equating it with the subjective 'feeling' — which is only the tip of the iceberg and can only be studied by asking humans.
2. States have defining properties beyond arousal and valence. Persistence (emotions outlast their triggering stimulus, unlike reflexes) and generalization (an emotion triggered in one situation carries into another, like a bad workday changing how you react to your screaming child) are core features that distinguish emotional states from simple reflexes.
3. Aggression is multifaceted, not one thing. Aggression describes behavior, not a single internal state — it can reflect anger, fear, or hunger (predatory aggression). Defensive rage and predatory aggression involve different hypothalamic circuits, and offensive aggression is actually rewarding to male mice, who will work to get the chance to attack a subordinate.
4. Estrogen, not testosterone, directly drives male aggression. The molecular marker for VMH aggression neurons is the estrogen receptor. Castrated mice can have fighting restored with an estrogen implant, bypassing testosterone entirely, because many of testosterone's effects are mediated by its conversion to estrogen via aromatase.
5. Fear dominates and shuts down aggression. Fear neurons sit directly adjacent to aggression neurons in the VMH; strong fear shuts down offensive aggression. Stimulating fear neurons stops a fight in its tracks, suggesting fear is hierarchically dominant over offensive aggression.
6. Love and war circuits sit side by side and can cross wires. VMH houses 'make war, not love' aggression neurons while the nearby medial preoptic area houses 'make love, not war' mating neurons; the dense interconnection between them may explain why mating can suddenly turn aggressive, and raised the question of whether sexual violence reflects 'crossed wires.'
7. Social isolation drives aggression through tachykinin. Two weeks of social isolation massively upregulates tachykinin-2 in the mouse brain, causing aggression, fear, and anxiety. A safe, already-tested drug (osonotan) that blocks the tachykinin-2 receptor reverses these effects and lets a previously murderous isolated mouse safely rejoin its cage-mates — suggesting solitary confinement is counterproductive for violent individuals.
8. Body and brain communicate bidirectionally to produce feelings. Emotional states drive sympathetic/parasympathetic activity and the vagus nerve, producing bodily sensations (the 'somatic marker' behind feelings); the vagus carries highly specific, organ-labeled afferent and efferent fibers that researchers are just beginning to decode.

Emotions as Internal States

Anderson frames emotion as a type of internal state, in the same category as arousal, motivation, and sleep. What unites these is that they change the input-to-output transformation of the brain — when you're asleep, you don't hear what you'd hear when awake. From this perspective, emotion is a class of state that controls behavior. Anderson argues this framing is valuable because it puts the focus on emotion as a neurobiological process rather than a psychological one.

He pushes back on equating emotion with feeling. Feeling is a subjective sense that can only be studied in humans, because the only way to discover what someone feels is to ask them, and humans are the only animals that can talk in a way we understand. Using his iceberg metaphor, the feeling is just the visible tip; the larger portion of emotion lies below the surface as measurable neurobiological processes that exist across species.

Persistence and Generalization

Anderson, working with Ralph Adolphs, has tried to expand the classical two-dimensional view of emotion (arousal and valence) by identifying additional components that distinguish emotional states from closely related motivational states. One key property is persistence: state-driven behaviors outlast their triggering stimulus, unlike reflexes, which terminate when the stimulus turns off (a doctor's hammer on the knee). His example: hearing a rattlesnake on a Southern California trail makes you jump, and your heart keeps pounding and palms keep sweating long after the snake slithers away, leaving you hyper-vigilant toward anything snake-like, even a stick.

Not all states persist. Hunger, for instance, disappears the moment you've eaten. But anger after a fight can keep you riled up long after the conflict ends. The second key property is generalization: an emotion triggered in one situation can carry over into another. His memorable example — coming home to a screaming child. After a good day at work you might soothe the child; after a bad day you might react very differently to the identical situation.

The Neurobiology of Aggression

Anderson emphasizes that 'aggression' refers to a description of behavior, not a single internal state. The same aggressive behavior could reflect anger, fear, or — in the case of predatory aggression — hunger. The pioneering work of Dayu Lin in his lab used optogenetics to activate specific neurons in the ventromedial hypothalamus (VMH) to evoke aggression in mice, building on the Nobel Prize-winning electrode studies of Walter Hess.

Hess originally described two types of aggression evoked from cats depending on electrode placement: 'defensive rage' (ears laid back, teeth bared, hissing) and 'predatory aggression' (ears forward, batting with the paw at a mouse-like object as if to catch and eat it). These map to fundamentally different circuits.

Anderson uses a pear-shaped model of the VMH: imagine a pear sitting on the ground. The fat part near the ground houses the aggression neurons, while the upper part of the pear houses fear neurons. Subsequent work by Dayu Lin (now at NYU) and her postdoc Annegret Falkner revealed that the fighting elicited by VMH stimulation is offensive aggression that is actually rewarding to male mice. The mice 'like it' — they will learn to poke their nose or press a bar for the opportunity to beat up a subordinate male. Aggression therefore carries a positive valence, and the overall 'state of aggressiveness' is multifaceted, depending on the type of aggression and involving different circuits.

Why Fear and Aggression Neurons Sit Side by Side

Huberman asks why neurons generating such divergent states would be positioned cheek-to-jowl. Anderson offers an evolutionary explanation: defensive behaviors and fear likely arose before offensive aggression, because animals must first defend themselves from predation before they can worry about social dominance ('who's going to be the alpha male'). Since brain regions and cell populations evolve by duplication and modification of pre-existing populations, this could explain their adjacency.

But he believes there is also a functional reason. Strong fear shuts down offensive aggression, whereas defensive aggression (at least in rats) is enhanced by fear — one of the big differences between the two. The two regions may be close together to facilitate inhibition of aggression by fear neurons. Anderson notes that deliberately stimulating the fear neurons at the top of the pear during a fight stops the fight dead and sends the animals to freeze in a corner — suggesting fear is hierarchically dominant over offensive aggression. He adds that VMH isn't just fight and flight; metabolic neurons are also mixed in.

Hydraulic Pressure and VMH as an Integration Hub

Drawing on Konrad Lorenz's concept of 'hydraulic pressure' toward behavior, Anderson distinguishes homeostatic, need-based behaviors (hunger, thirst, temperature regulation) governed by a thermostat-like set-point model from drives that build up pressure to act. He frames accumulated 'hydraulic pressure' as gradual increases in neural activity in specific brain regions. Scott Sternson and others showed that in the feeding region of the hypothalamus, the hungrier an animal gets, the higher the neural activity — and eating makes it drop instantly.

For aggression, Anderson's data show that the more strongly you optogenetically drive the VMH, the more of a hair-trigger the animal becomes, requiring less provocation to fight. He describes the VMH as both an antenna and a broadcasting center: it projects to about 30 brain regions and receives input from about 30. Like a satellite dish, it takes in information across sensory modalities (smell, vision, mechanosensation), synthesizes it into a low-dimensional representation of the 'pressure to attack,' and broadcasts it across the brain to coordinate the many systems needed for aggression. Because aggression is risky — an animal could lose and be killed — the brain must constantly make a cost-benefit analysis of whether to continue or back off.

Hormones and Aggression: The Estrogen Surprise

Huberman raises the common myth that testosterone makes animals aggressive while estrogen makes them placid and emotional, noting nothing could be further from the truth. When Anderson's lab finally identified the molecular marker for the VMH aggression neurons, that marker turned out to be the estrogen receptor. Other labs showed that the estrogen receptor in adult male mice is necessary for aggression — knock out the gene in the VMH and the mice don't fight.

Work from Nirav Shah at Stanford (a former PhD student of Anderson's) demonstrated that when a castrated mouse loses its ability to fight, fighting can be rescued not only with a testosterone implant but also with an estrogen implant, completely bypassing the requirement for testosterone. This is because many — though not all — of testosterone's effects are mediated by its conversion to estrogen through aromatization, carried out by the enzyme aromatase. Anderson notes that listeners may recognize aromatase because aromatase inhibitors are widely used in women as adjuvant chemotherapy for breast cancer.

Female Aggression and Sex-Specific Neurons

Anderson's lab has studied female aggression in both mice and fruit flies. A striking distinction: male mice are ready to fight at the drop of a hat, while female mice only fight when they are nurturing and nursing pups after delivering a litter, during which they become hyper-aggressive. Once the pups are weaned, the aggressiveness disappears. The same female that responds to a male with sexual receptivity as a virgin will, after having pups, attack that same male instead of mating.

Work from Anderson's student Mengyu Liu showed that within the female VMH there are two clearly divisible subsets of estrogen-receptor neurons: one controls fighting and the other controls mating. This reveals deep complexity in sex-specific wiring. The male VMH contains both male-specific aggression neurons and generic aggression neurons, while the female VMH mating cells are found only in females and not in the male brain. Anderson's lab is working to determine what these sex-specific populations do, but their existence indicates a mechanism by which the sexes show different behaviors.

Mating, Aggression, and Crossed Wires

Huberman observes the wide range of mating behaviors across species and humans, some with aggressive components and some without. Anderson, not a naturalist, declines to speak to species-specificity but notes that lions he's observed in Africa show a biting component during mating. A surprise from his lab: within the VMHvl aggression population in males, there is a subset of neurons activated by females during male-female mating encounters. Evidence suggests these female-selective neurons are part of mating behavior — shutting them down impairs mating effectiveness. What stimulating them does remains unknown, since there's no way to activate them selectively without also activating the male aggression neurons.

Anderson explains that VMH is not the traditional brain region for male sexual behavior — that's the medial preoptic area, where his lab showed neurons definitively stimulate mating. Remarkably, if those mating neurons are activated in a male while it is attacking another male, the male will stop fighting, start 'singing' to the other male, and try to mount him — until the neurons are switched off. He calls these the 'make love, not war' neurons, while VMH holds the 'make war, not love' neurons. The two nuclei are very close and densely interconnected, with both antagonistic and possibly cooperative interactions. The balance between them at any moment in a mating encounter could determine whether 'coital bliss' suddenly turns into a snap, growl, and baring of fangs — the wiring is there for that to happen.

When Anderson's lab made this discovery, it raised the question in his mind of whether some serial rapists or perpetrators of sexual violence might at some level have their wires crossed — with states that are supposed to be separate and mutually antagonistic instead being intertwined and actually rewarding and reinforcing.

The Periaqueductal Gray (PAG) and Pain Modulation

Anderson likens the PAG to an old-fashioned telephone switchboard: incoming calls must be plugged into the right hole to route information to the correct recipient. Nearly every type of innate behavior has had the PAG implicated. In cross-section the PAG resembles the water in a toilet bowl, and if you imagine a clock face projected onto it, it has sectors from 1 to 12 (maybe more). Different neurons from the hypothalamus project to different sectors, suggesting a topographic arrangement along both the dorsal-ventral and medial-lateral axes that may determine which behavior is emitted — though this has not yet been fully mapped.

On pain, Anderson addresses Huberman's martial-arts observation that getting punched hurts little during a fight but much more afterward. This reflects the well-known phenomenon of fear-induced analgesia: in a high state of fear (such as defending oneself), pain responses are suppressed. The mechanisms aren't fully understood, but he notes the adrenal medulla releases a peptide that controls fight-or-flight responses and also has analgesic activity. When Huberman asks what it is, Anderson names it: bovine adrenal medullary peptide of 22 amino acid residues (BAM22). He knows of it because it activates a pain-related receptor his lab discovered years ago — initially thought to promote pain, but it turned out to inhibit pain, acting as an endogenous analgesic.

Anderson doesn't know whether this analgesia occurs during offensive aggression or mating, or whether it acts in the PAG or further down in the spinal cord — the PAG is continuous with the spinal cord, so influences on pain could act at many levels. He carefully distinguishes between things that are genuinely unknown (within his area of expertise) and things that may be known but lie outside his knowledge base.

Tachykinin, Social Isolation, and a Promising Drug

Tachykinins are a family of related neuropeptides — short pieces of protein directly encoded by genes active in specific neurons, distinct from small-molecule transmitters like dopamine and serotonin. When the neurons fire, the peptides are co-released with classical transmitters like glutamate. Tachykinin-1 (substance P) is famously implicated in promoting inflammatory pain. In an unbiased peptide screen, Anderson's lab found that Drosophila tachykinin neurons strongly promote aggression when activated, in a manner dependent on tachykinin release.

Crucially, social isolation increases aggressiveness across social animals — flies, mice, and humans. Anderson notes this makes solitary confinement of a violent prisoner 'the worst, most counterproductive thing you could do.' In flies, social isolation raises brain tachykinin levels, and silencing the gene prevents isolation from increasing aggression.

Extending this to mice, former postdoc Moriel Zelikowsky (now at the University of Utah) found that two weeks of social isolation produces a massive upregulation of tachykinin-2 in the brain — so much that when the peptide is genetically tagged with jellyfish-derived green fluorescent protein, the isolated mouse's brain glows green. This increase is responsible for isolation-induced increases in aggression, fear, and anxiety.

Osonotan: A Shelved Drug With Striking Effects

Drugs that block the tachykinin receptor were tested in humans and abandoned for lack of efficacy in the conditions they were studied for. But given to socially isolated mice, the drug osonotan (which blocks tachykinin-2) blocks all effects of isolation — the aggression, increased fear, and increased anxiety. Zelikowsky described the treated mice as simply looking 'chill.' Importantly, it is not a sedative; the mice don't fall asleep.

The most dramatic result: once a mouse is socially isolated and becomes aggressive, it can never be returned to its cage with its litter-mate brothers because it will kill them all overnight. But a mouse given osonotan can be safely returned and will not attack, seeming content thereafter. Anderson emphasizes the drug has a very good safety profile and has been eager to get pharmaceutical companies to test it in humans experiencing social-isolation stress or bereavement stress — but for economic reasons it has been very difficult to find anyone willing to run that trial.

The Body, the Vagus Nerve, and the Feeling of Emotion

Huberman raises the heat-map diagram in Anderson and Adolphs' book showing where people subjectively report feeling emotions in their bodies (anger, sadness, calm, loneliness, etc.), cautioning that those maps came from self-report, not physiological measurement. Anderson connects this to Antonio Damasio's somatic marker hypothesis: the subjective feeling of an emotion is partly associated with sensations in particular body parts — the gut, the heart.

If a physiology underlies these heat maps, it could reflect increased blood flow to different structures, driven by bidirectional brain-body communication via the sympathetic and parasympathetic nervous systems, which control heart rate and blood pressure. These autonomic neurons receive input from the hypothalamus and other central brain regions; when the brain enters a particular state, it activates these neurons, which act on the heart and blood vessels, and the resulting bodily changes feed back to the brain through sensory systems.

A large part of this bidirectional communication runs through the vagus nerve, a bundle of fibers exiting the skull and innervating the heart, gut, and other visceral organs. Its fibers are both afferent and efferent — afferent fibers sense bodily events (which is why a tense stomach 'tied in knots' is the vagus sensing gut-muscle contraction), while efferent information from the brain influences peripheral organs. Anderson notes that in just the past six months, labs have begun decoding the vagus's component fibers and found striking specificity, almost like color-coded, labeled lines — specific vagal nerves for the lung controlling breathing, others for the gut and other organs. How these vagal afferents contribute to emotional states is a question researchers are just beginning to explore, and new tools to selectively turn vagal fibers on or off will let scientists test how each affects emotional behavior. Anderson stresses this brain-body connection — recognized even by Darwin — is a central feature of emotional states and likely underlies our subjective feelings.

The Importance of the Unknown

Closing the conversation, Anderson emphasizes the value of acknowledging what is not known. He notes that only a little is understood in this field, and that highlighting the unknowns is essential because they define what the next generation of neuroscientists must solve. He hopes the discussion will attract young people into the field, given its importance for understanding mental illness, mental health, and psychiatry. His central argument: figuring out how emotion systems are causally controlled is a prerequisite to improving on current psychiatric treatments, and that progress depends on the next generation entering the field.