Stanford's Huberman Links Brain Estrogen to Aggression via Light Signals

斯坦福Huberman：光信号通过脑内雌激素引发攻击行为 季节性日照减少会加剧攻击行为，因为升高的皮质醇和降低的五羟色胺会激活下丘脑腹内侧带有雌激素受体的神经元，从而诱发躯体敌意。 本期节目将攻击行为解构为不同类别，打破了“攻击只是悲伤的一种形式”这一迷思，表明它依托于独特的大脑回路运作。结合历史模型与现代神经生物学，节目解释了下丘脑腹内侧如何作为主要的结构驱动中枢，在特定体内条件下由睾酮转化为雌激素时被触发。讨论重点强调了日照时间缩短等环境因素如何导致皮质醇升高和五羟色胺降低，从而积聚引发过度反应的体内“水压”。最后，节目提供了一些可操作的方案，例如最大化日照接触、利用桑拿热疗，以及补充南非醉茄或乙酰左旋肉碱，以系统性降低压力激素并遏制冲动或攻击行为。 攻击行为并非单一的行为模式，而是划分为三个不同的类别：反应型攻击、主动型攻击和间接攻击。 (0:00) 大众心理学中常见“攻击只是悲伤”的观点在生物学上是错误的，因为攻击和悲伤的神经回路截然不同。 (1:43) 攻击行为表现为一个具有开头、中间和结尾的主动行为序列，在历史上曾被Konrad Lorenz建模为“水压”的积聚。 (3:10) 下丘脑腹内侧（VMH）总共仅由约3,000个神经元组成，是产生躯体攻击和内心愤怒的结构源头与充分脑区。 (6:41) 光遗传学测绘表明，表达雌激素受体的特定VMH神经元亚群直接负责在其他社交行为之上触发攻击行为。 (9:25)

Andrew Huberman explains that aggression is a sequential, biologically mediated neural process driven primarily by estrogen receptor activation in the ventromedial hypothalamus—not testosterone—and is heavily regulated by seasonal light, stress hormones, and targeted behavioral interventions. Neural Circuitry of the Ventromedial Hypothalamus (6:41) Aggression is not a monolithic state or an expression of sadness, but an active behavioral sequence unfolding like notes on a piano. Grounded in Konrad Lorenz’s concept of fixed action patterns and hydraulic pressure, this behavior originates in specific neural clusters. Walter Hess demonstrated that electrical stimulation of the ventromedial hypothalamus (VMH)—a tiny structure of roughly 3,000 neurons (1,500 per side)—is sufficient to instantly drive passive animals into intense rage, which halts the moment stimulation ceases. Subsequent optogenetic research by David Anderson and Dayu Lin showed that activating estrogen-receptor-bearing VMH neurons causes male mice to instantly abort mating and attack females or even inanimate rubber gloves. Downstream, the VMH signals the periaqueductal gray (PAG), a region producing endogenous opioids that provide localized pain relief during combat. The PAG coordinates primitive physical outputs, such as jaw muscles involved in biting and uncoordinated striking. Estrogen and the Testosterone Rage Myth (15:54) Huberman directly challenges the cultural belief that testosterone causes violent aggression. Testosterone primarily increases competitiveness, proactivity, and effort; it amplifies an individual's baseline disposition, making aggressive people more aggressive and benevolent people more altruistic. The direct chemical trigger for violent neural activation is actually estrogen. Through the action of the aromatase enzyme, testosterone is converted into estrogen within the brain. This locally synthesized estrogen binds to the estrogen receptors located on VMH neurons to evoke aggressive displays. Both mice and humans lacking functional aromatase exhibit severe reductions in aggressive behavior, even when their testosterone levels are artificially elevated. Photoperiod and Cortisol Modulate Irritability (19:56) The capacity of estrogen to trigger aggressive circuitry is heavily dependent on photoperiod, or daylight exposure. Citing work by Trainor and colleagues published in the Proceedings of the National Academy of Sciences, Huberman notes that long-day conditions block estrogen from triggering aggression. In contrast, short winter days increase melatonin, decrease dopamine, and elevate cortisol, establishing a chemical environment primed for irritability and aggressive outbursts. Reactivity is governed by the sympathetic nervous system, where elevated cortisol and adrenaline prepare the body for rapid movement and lower the threshold for hostility. While genetic variants can heighten the sensitivity of estrogen receptors, environmental conditions—such as light deprivation from working indoors under fluorescent bulbs—substantially dictate whether those genetic predispositions manifest as chronic aggression. Behavioral Protocols and Carnitine Interventions (24:23) Mitigating internal hydraulic pressure requires lowering baseline cortisol through lifestyle and environmental habits. Practical protocols include maximizing natural sunlight viewing throughout the day and using 20-minute heat exposure in a sauna at 80°C to 100°C (or a hot bath) to suppress cortisol. For supplementation, ashwagandha potently inhibits cortisol, though Huberman advises cycling it for two weeks on followed by two weeks off to avoid disrupting broader endocrine pathways. To address impulsivity and aggression in neurodevelopmental contexts, Huberman highlights a randomized, double-blind, placebo-controlled, double-crossover study evaluating acetyl-L-carnitine in children with ADHD. Supplementation produced significant drops in total problem scores, delinquency, and aggressive outbursts, with therapeutic efficacy confirmed by measured shifts of carnitine levels in the bloodstream. Huberman emphasizes that controlling aggression requires a multifaceted approach rather than relying on a single nutritional or behavioral cure. Individuals can reliably lower internal hydraulic pressure and maintain adaptive social engagement by combining light management, heat exposure, stress reduction, and targeted supplementation.

斯坦福大学神经生物学教授 Andrew Huberman 指出，攻击行为是由高度特异的神经环路和生化机制驱动的动态生物学过程，而非笼统的情绪爆发或悲伤的衍生形式。攻击性在体内如同不断蓄积的“液压”，受脑内雌激素转化、环境光周期及应激状态共同调节，个体可通过调控光照、热应激及营养补充等综合手段有效缓解冲动反应。 攻击行为的神经中枢与固定动作模式 (6:41) Huberman 澄清了流行心理学中“攻击性本质是悲伤”的误区，指出同行评审文献证实攻击环路与悲伤、哀恸的脑区完全独立。基于 Konrad Lorenz 的经典理论，攻击并非静止状态，而是具有起止进程、类似击打琴键的“动词”。现代神经生物学定位了该行为的解剖学核心：Walter Hess 早期在猫脑实验中发现，仅刺激由两侧共约 3000 个神经元组成的腹内侧下丘脑（VMH），便足以瞬间诱发极度暴怒并在断电后立即恢复平静。这一现象在小鼠与人类研究中均得到重复。 加州理工学院 David Anderson 实验室与纽约大学 Dayu Lin 进一步利用光遗传学技术证实，VMH 内表达雌激素受体的特定神经元是激化攻击的直接开关。在实验中，正在交配的雄性小鼠在受到蓝光刺激的瞬间会立即转变为致命撕咬，甚至对无生命的充水橡胶手套发起猛烈攻击。该环路向下投射至导水管周围灰质（PAG），PAG 不仅激活控制咬合与肢体挥动的原始战斗肌肉，还会释放内源性阿片类物质以提供适应性的镇痛保护，形成了生物学上高度刻板的“固定动作模式”。 雌激素转化诱发攻击与睾酮的真实机制 (15:54) 大众文化普遍将暴力和愤怒归咎于睾酮，但 Huberman 强调实验证据推翻了这一假设：睾酮本身并不直接增加攻击性，其核心作用是提升竞争主动性、促进行为努力。在善意个体身上，增加睾酮甚至会放大其利他行为。真正触发攻击环路的生物学物质是脑内芳香化酶将睾酮转化为雌激素产物，进而与腹内侧下丘脑中表达雌激素受体的神经元结合。基因敲除芳香化酶的小鼠和人体均表现出整体攻击性的急剧下降，且不受高浓度游离睾酮的影响。 男性之所以依赖睾酮诱发攻击冲动，是因为其睾丸分泌的循环雌激素基线较低，必须依靠睾酮作为前体分子在脑组织局部芳香化转化为雌激素。因此，攻击行为的生化扳机并非雄性激素本身，而是脑内局部雌激素受体的结合与激活状态。 日照光周期与皮质醇对攻击阈值的调谐 (19:56) 雌激素是否诱发攻击行为严格依赖于机体所处的环境光周期。Trainor 等人发表在《美国国家科学院院刊》（PNAS）的研究表明，光照时长通过褪黑素、多巴胺和皮质醇的周期性分泌重塑机体生化内环境。在日照充足的长日照环境下，即便人为提高雌激素水平，也无法激活攻击环路；然而在短日照的冬季环境中，多巴胺分泌受抑，机体因应对低温环境中的病原体而长期维持高水平的皮质醇分泌。 当应激激素皮质醇居高不下，而与心理安适感相关的血清素偏低时，神经系统会处于高度戒备与易怒状态，此时雌激素便极易触发攻击行为。这一现象印证了 Lorenz 的“液压模型”：外界负面刺激与内部神经递质、激素环境持续向密闭容器中“注水”，随着内部生理压力升高，个体对轻微挑衅的容忍阈值急剧降低，最终演变为言语或躯体冲突。 调控神经反应性与冲动的多维度干预策略 (24:23) 自主神经系统的交感神经兴奋会协同皮质醇与肾上腺素释放，使机体进入预备反击的颤抖警觉状态。为重置神经系统的触发阈值，Huberman 建议在清晨和日间主动接触安全阳光以模拟长日照状态，避免在室内荧光灯环境下长期暴露而陷入短日照生物学陷阱。在生理调节层面，每周进行 20 分钟 80°C 至 100°C 的桑拿浴（或热水浴）能显著下调皮质醇水平；南非醉茄（Ashwagandha）作为皮质醇抑制剂可短期使用，但为避免干扰其他内分泌通路，建议采取服用两周停用两周的周期策略。 针对病理性冲动与多动障碍（ADHD），一项采用随机双盲安慰剂对照交叉设计的临床试验证实，补充乙酰左旋肉碱（Acetyl-L-carnitine）可显著改善儿童的行为问题总分，大幅降低注意缺陷、越轨行为及躯体攻击性，且血检数据确认了血液中肉碱水平与心理行为改善之间的明确生理关联。Huberman 指出，不存在消除攻击冲动的单一手段，唯有整合光照节律、体温干预、营养补充与环境压力管理，方能有效卸除体内的生物学液压。 Huberman 总结认为，攻击性是基因易感性、环境光周期与内部神经化学环境动态交织的产物。尽管通过光照管理、皮质醇控制和特定营养素能够有效降低非适应性攻击冲动，但如何根据个体的神经遗传差异制定长期的精准干预标准，仍是神经生物学有待进一步解决的课题。

[1:43] Andrew Huberman: Many of you have probably heard the statement that I believe arises from pop psychology, not from formal academic psychology, that aggression is just sadness. [9:25] Andrew Huberman: The male mouse ceases from trying to mate with the female mouse and immediately tries to kill the female mouse. He starts attacking her. Then she turns off the light, the male stops and goes back to trying to mate with the female mouse. [15:54] Andrew Huberman: Testosterone does not increase aggressiveness. [31:43] Andrew Huberman: very seldom, if ever, will there be one supplement or one nutritional change or even one behavioral change that's going to completely shift an individual from being aggressive and impulsive. [33:19] Andrew Huberman: and as always thank you for your interest in science.

[0:00] Welcome to Huberman Lab Essentials, [0:02] where we revisit past episodes for the [0:04] most potent and actionable science-based [0:06] tools for mental health, physical [0:08] health, and performance. [0:11] I'm Andrew Huberman, and I'm a professor [0:13] of neurobiology and ophthalmology at [0:15] Stanford School of Medicine. [0:17] Today, we are discussing aggression. [0:20] I'm going to explain to you that there [0:21] are several different types of [0:22] aggression. For instance, reactive [0:24] aggression versus proactive aggression, [0:26] meaning sometimes people will be [0:28] aggressive because they feel threatened [0:30] or they are protecting those that they [0:32] love who also feel threatened. There's [0:34] also proactive aggression where people [0:36] go out of their way to deliberately try [0:38] and harm others. And there is indirect [0:41] aggression, which is aggression not [0:43] involving physical violence. For [0:45] instance, shaming people and things of [0:47] that sort. It turns out that there are [0:49] different biological mechanisms [0:51] underlying each of the different types [0:52] of aggression. And today, I will define [0:54] those for you. I'll talk about the [0:56] neural circuits in the brain and body [0:57] that mediate each of the different kinds [0:59] of aggression. Talk about some of the [1:01] hormones and peptides and [1:02] neurotransmitters involved. I promise to [1:04] make it all accessible to you even if [1:06] you do not have any biology or science [1:08] background. I'm certain that by the end [1:10] of the episode, you will come away with [1:11] a much more thorough understanding of [1:13] what this thing that we call aggression [1:15] really is. And when you see it in other [1:17] people, I think it will make more sense [1:20] to you. And when you observe it in [1:22] yourself or the impulse to engage in [1:24] aggression, verbal or physical or [1:26] otherwise, [1:27] I hope that you'll understand it better [1:29] as well. And of course, the tools that I [1:30] will describe should allow you to [1:33] modulate and control aggressive [1:35] tendencies or predispositions to [1:37] aggressiveness and just generally be [1:39] able to engage with people in a more [1:41] adaptive way overall. The context of [1:43] aggression really matters. So, there are [1:45] instances where aggression is adaptive. [1:48] For instance, a mother protecting her [1:50] children. Of course, other forms of [1:52] aggression like unprovoked proactive [1:55] aggression, somebody simply being [1:57] violent to somebody else [1:59] even when unprovoked. Most of us cringe [2:01] when we see that kind of behavior. It [2:03] can even evoke aggression in people when [2:05] they observe that kind of behavior. Many [2:07] of you have probably heard the statement [2:09] that I believe arises from pop [2:11] psychology, not from formal academic [2:13] psychology, that [2:15] aggression is just sadness. It's a form [2:18] of sadness that's amplified and it shows [2:20] up as aggression. But when we look at [2:22] the underlying biology and the [2:24] peer-reviewed literature on this, [2:26] nothing could be further from the truth. [2:28] We have distinct circuits in the brain [2:30] for aggression versus grief and [2:33] mourning. Those are non-overlapping. [2:36] Now, that doesn't mean that you can't be [2:37] sad and aggressive or in a state of [2:39] mourning and aggressive at the same [2:40] time. But the idea that sadness and [2:43] aggression are one in the same thing is [2:45] simply not true. [2:47] And by understanding that, or perhaps by [2:49] understanding that irritability and [2:51] aggression are not the same thing, [2:53] you'll be in a much better position to [2:55] apply some of the tools that we will [2:56] talk about in this episode in order to [2:58] be able to reduce, or eliminate, or if [3:02] it's adaptive to you, to modulate [3:04] aggression. And yes, there are cases [3:05] where modulating your aggression, in [3:07] some cases even amplifying aggression, [3:10] can be adaptive. One of the names that's [3:12] most associated with the formal study of [3:14] aggression is none other than Konrad [3:17] Lorenz. Konrad Lorenz [3:20] studied so-called imprinting behaviors [3:22] and fixed action pattern behaviors. [3:25] Patterns of behavior that could be [3:26] evoked by a single stimulus. The idea [3:29] that you can get a whole category of [3:31] behaviors, like looking to somebody for [3:33] comfort and only them. The idea that [3:35] that you could get a huge category of [3:37] different behaviors in a bunch of [3:38] different contexts triggered by just the [3:40] presence of that person [3:42] is remarkable because what it suggested [3:44] and what turns out to be true is that [3:46] there are neural circuits, not just [3:48] individual brain areas, but collections [3:50] of brain areas that work together to [3:51] engage a pattern of behaviors. And [3:54] that's the first fundamental principle [3:57] that we need to define today. That when [3:59] we talk about aggression, we're talking [4:01] about activation of neural circuits, not [4:04] individual brain areas, but neural [4:06] circuits that get played out in sequence [4:08] like keys on a piano. [4:10] But that playing out in sequence means [4:12] that aggression is a verb. It has a [4:14] beginning, a middle, and an end. And [4:17] it's a process. It's not an event. And [4:19] as you'll see, that turns out to be very [4:21] important in terms of thinking about how [4:23] one can halt aggression, [4:25] prevent it from happening before it's [4:27] initiated, [4:28] or [4:29] maybe even prolonging aggression if [4:31] that's what's needed. Now, Konrad Lorenz [4:33] had no real knowledge of neural [4:35] circuits. I mean, obviously he knew [4:36] there was this thing that we call a [4:37] brain and a nervous system. [4:39] And he knew that there were chemicals in [4:41] the brain and hormones and things of [4:43] that sort that were likely to play a [4:45] role. But he really didn't take any [4:47] measures to define what the neural [4:49] circuits were. But he did think about [4:51] what sorts of underlying processes could [4:54] drive something like aggression. And he [4:57] talked about one particular feature [4:59] that's especially important. And that's [5:01] this notion of a pressure. The idea that [5:04] yes, certain hormones will bias somebody [5:08] or an animal to be aggressive. Certain [5:10] neurotransmitter states, and you'll [5:12] learn what those are today, will bias [5:14] somebody to be more or less aggressive. [5:16] And yes, of course, there will be [5:18] historical features based on their [5:19] childhood, etc., etc. [5:21] He understood that there would be a [5:23] constellation of things that would drive [5:25] people to be aggressive. [5:27] And he described a so-called pressure, [5:28] almost like a hydraulic pressure. Just [5:30] think about fluid pressure in a small [5:32] container being pushed, pushed, pushed [5:34] until the can or the container is ready [5:35] to explode. [5:37] And how multiple features, multiple [5:39] variables could impinge on that and [5:42] create that pressure. [5:43] It turns out that's exactly the way this [5:45] system works. There is no single brain [5:47] area that flips the switch for [5:49] aggression. Although we'll soon talk [5:51] about a brain structure that generally [5:53] houses the propensity and the output of [5:55] aggression. [5:57] This notion of a hydraulic pressure that [5:59] can drive us toward aggressive behavior [6:02] or conversely can be [6:05] very low pressure and keep us in a state [6:07] of non-reactivity, maybe even passivity [6:10] or submissiveness is a very important [6:12] feature because it really captures the [6:14] essence of how neural circuits work when [6:17] we're talking about primitive behaviors [6:18] generally and you can start to notice [6:21] this in yourself and in others. [6:23] You can start to notice when you are [6:25] veering toward aggression or when [6:27] someone is veering toward aggression [6:29] verbal or physical. [6:31] Now that veering is the build-up of this [6:34] hydraulic pressure that Lorenz was [6:36] referring to and it really does have an [6:38] underlying biological basis. Now it was [6:41] some years later [6:43] that the first experiments came along [6:45] which really started to identify the [6:48] brain areas and the biological so-called [6:50] pressures that can induce aggressive [6:53] behavior. [6:54] And the person that really gets credit [6:55] for this is [6:57] a guy by the name of Walter Hess [6:59] who at that time was working on cats and [7:02] I know that when say working on cats a [7:04] lot of people will cringe, a lot of [7:05] people have cats as pets and certainly [7:07] cats can be delightful. Some people like [7:09] them more, some people like them less. [7:10] Most people cringe at the idea of doing [7:12] experiments on cats. In the time of Hess [7:15] very few laboratories worked on mice. [7:16] Most laboratories worked on cats or [7:19] rats. So when I say he was working on [7:20] cats, I realize that probably evokes [7:22] some negative emotions in some of you, [7:24] maybe even aggression in some of you. [7:26] What we can do however is look at the [7:29] data and make use of the data in terms [7:32] of our understanding. [7:34] What Hess did was he had cats that were [7:37] awake and he was able to lower [7:39] stimulating electrode into the brain. [7:40] Now keep in mind that the brain does not [7:42] have any pain sensors. So, after a small [7:44] hole is made in the skull, electrodes [7:46] are lowered into the brain. This is [7:47] what's done commonly in human [7:49] neurosurgery. He was trying to identify [7:51] brain regions [7:53] that could generate [7:55] entire categories of behavior. [7:57] Eventually, his electrode landed in a [7:59] site, and he provided electrical [8:01] stimulation to the cat that caused this [8:04] otherwise passive, purring, relaxing cat [8:09] to suddenly go into an absolute rage [8:12] when he stimulated this particular brain [8:13] area. And the fact that when he turned [8:15] off the stimulation of this particular [8:17] brain area, the cat very quickly, within [8:20] seconds, went back to being passive, [8:22] calm kitty. And later experiments done [8:25] in mice, but also in humans, confirmed [8:27] that indeed stimulation of this brain [8:29] area [8:30] evoked not just behavioral aggression, [8:33] but also subjective feelings of [8:35] aggression and anger. So, what was this [8:37] incredible brain area? The so-called [8:39] VMH, [8:41] or ventromedial hypothalamus. The [8:43] ventromedial hypothalamus [8:45] is a nucleus, meaning a small collection [8:48] of neurons, only about [8:50] 1,500 neurons on one side of your brain, [8:53] and a matching 1,500 neurons on the [8:55] other side of your brain, and that [8:57] combined 3,000 neurons or so is [9:00] sufficient to generate aggressive [9:03] behavior of the sort that Hess [9:07] observed in the cat. And believe it or [9:09] not, when you see somebody who's in an [9:11] act of rage or in an act of verbal [9:14] aggression, or in an act of defensive [9:17] aggression, protecting their family or [9:19] loved ones or country, etc., almost [9:21] certainly [9:23] those neurons are engaged in that [9:24] behavior. Experiments done by David [9:27] Anderson's lab at Caltech [9:29] were really the first to parse the fine [9:31] circuitry and to really show that the [9:34] ventromedial hypothalamus is both [9:35] necessary and sufficient for aggressive [9:37] behavior. What they did was [9:40] they identified where the ventromedial [9:42] hypothalamus was in the mouse. That was [9:44] pretty straightforward to do. It was [9:45] sort of known before they started these [9:46] experiments. And then they analyzed [9:49] which genes [9:52] meaning which DNA, which of course [9:54] becomes RNA and RNA becomes protein. [9:57] Which DNA and therefore which proteins [9:59] are expressed in particular cells of the [10:03] ventromedial hypothalamus. [10:05] And it turns out that there's a [10:06] particular category of neurons in the [10:09] ventromedial hypothalamus [10:11] that make an estrogen receptor. [10:14] And it is those neurons in particular [10:17] that are responsible for generating [10:19] aggressive behavior. [10:21] How did they know this? Well, they used [10:22] a tool that's actually been described by [10:24] a previous guest of this podcast. We had [10:26] an episode with the psychiatrist and [10:28] bioengineer and my colleague at Stanford [10:30] School of Medicine, Karl Deisseroth. He [10:32] and others have developed tools that [10:35] allow people to control the activity of [10:38] neurons essentially by remote control by [10:40] shining light on those neurons. So, in [10:42] the context of an experiment on a mouse, [10:43] which is what David's lab did, and these [10:45] were the beautiful experiments of Dayu [10:47] Lin, who's now in her own laboratory at [10:48] New York University, put a little fiber [10:50] optic cable down into the hypothalamus [10:52] of the mouse. The mouse is able to move [10:54] around in its cage, freely moving. [10:57] Even though it has a little tether, this [10:58] little wire, it's a very thin wire. And [11:00] that little thin wire is actually a [11:02] little what we call optrode. And the [11:03] experimentalist in this case, Dayu, was [11:06] able to stimulate [11:07] the [11:09] turning on of a little bit of [11:11] blue light. And that blue light [11:12] activated only those estrogen receptor [11:16] neurons in only the ventromedial [11:19] hypothalamus. And the way she was able [11:20] to do that is she had introduced a gene [11:23] that had been developed by our friend [11:25] Karl Deisseroth [11:26] that allows light to trigger electrical [11:30] activity in those neurons. So, if any of [11:31] that is confusing or if all of that is [11:33] confusing, here's the experiment. [11:34] There's a mouse in a cage. [11:36] Has a little wire coming out of its [11:37] head. It doesn't notice, believe it or [11:39] not. We know this cuz it's still eating [11:41] and mating and doing all the things that [11:42] mice like to do on daily basis and [11:44] sleeping, etc. [11:46] And the mere pressing of a button will [11:48] activate a little bit of light released [11:51] at the end of that wire. That light [11:52] activates particular neurons. In this [11:54] case, it's the estrogen receptor [11:56] containing neurons in only the [11:57] ventromedial hypothalamus. [11:59] A large number of experiments were done, [12:01] but the first experiment really was to [12:03] put the male mouse in with a female [12:05] mouse who's in the so-called receptive [12:07] phase of estrus. That is, she will allow [12:10] mating. And he starts mating with her. [12:13] And they go through the standard [12:14] repertoire of mating behaviors that you [12:17] observe in mice. [12:19] Mounting, thrusting, intromission, as [12:21] it's called in the mouse sex world. Um [12:24] well, I guess I don't know what the mice [12:24] call it, but that's what the [12:25] experimenters call it. And then [12:28] afterwards, uh he will dismount. But, [12:30] about halfway through the behavior, Di [12:33] turned on the light to stimulate these [12:36] estrogen receptor containing neurons [12:38] only in the male mouse. And what she [12:40] observed was incredibly dramatic. [12:43] The male mouse ceases from trying to [12:45] mate with the female mouse and [12:46] immediately tries to kill the female [12:48] mouse. He starts attacking her. Then she [12:50] turns off the light, the male stops and [12:52] goes back to trying to mate with the [12:53] female mouse. So, I'm sure all of this [12:55] was very confusing and disturbing to the [12:57] female mouse. Nonetheless, that was the [12:59] repertoire. These are such dramatic [13:01] shifts in behavior triggered only by the [13:03] activation of only the small set of [13:05] neurons within the ventromedial [13:07] hypothalamus. The shift in behavior is [13:09] almost instantaneous. Occurs within [13:12] seconds, if not milliseconds, [13:14] thousandths of a second. [13:16] The next experiment that she did was to [13:18] put a male mouse with this [13:21] stimulation with light capability in its [13:24] ventromedial hypothalamus into a cage [13:25] alone, but with a rubber glove filled [13:28] with air or water. Then she stimulates [13:30] the activation of these ventromedial [13:32] hypothalamus neurons, and the mouse [13:34] immediately tries to kill the glove. It [13:37] goes into a rage attacking the glove as [13:39] if it were another mouse or some other [13:41] animate object, but of course it's an [13:43] inanimate object. It's just a rubber [13:45] glove. She stops the stimulation and the [13:47] mouse immediately goes to back to being [13:48] completely calm or at least not [13:50] attacking. Again, we don't know what the [13:52] mouse was feeling. Subsequent [13:53] experiments done by Dayu Lin in her own [13:55] laboratory and other laboratories have [13:58] shown that the ventromedial hypothalamus [14:00] is connected with a bunch of other brain [14:01] areas. One of them [14:03] that I want to call out now is the [14:05] so-called PAG, the periaqueductal gray [14:08] nucleus. This is a large structure in [14:10] the back of the brain that houses things [14:12] like neurons that can create opioids. [14:15] We all know of the opioid crisis, but [14:16] these are [14:17] neurons that can produce endogenous, [14:19] means made by the body, [14:22] chemicals that can cause pain relief. [14:25] You could understand why that might [14:26] occur in a circuit for aggression, [14:28] right? Even if one is the aggressor, [14:31] it's likely that they may incur some [14:33] physical damage and they'd want some [14:34] pain relief. [14:37] The PAG also is connected to a number of [14:39] neural circuits that eventually, through [14:42] several processing stages stations, [14:44] excuse me, arrive at things like the [14:46] jaws. And in fact, stimulation of the [14:48] ventromedial hypothalamus can evoke [14:50] biting and aggressive biting behavior. [14:53] Now, aggressive biting behavior is [14:54] particularly interesting because in [14:57] humans, and especially in human [14:58] children, [14:59] biting is something that [15:01] while young children might do as a form [15:04] of aggression, tends to disappear pretty [15:06] early in childhood. And if it doesn't, [15:09] it's often seen as a mark of pathology. [15:12] I think there is general agreement in [15:13] the psychology community and the [15:15] psychiatric community that past a [15:16] certain age, the using of one's teeth to [15:18] impart aggressive aggression and damage [15:20] on others is a particularly primitive [15:23] and troubling, or at least for the [15:25] observer or the person that experiences [15:27] a pretty disturbing event. [15:29] Dyu's lab has shown that activation of [15:32] the ventromedial hypothalamus triggers a [15:33] downstream circuit in the periaqueductal [15:35] gray, which then triggers a whole other [15:38] set of circuits of fixed action [15:40] patterns. Here we are back to Lorenz [15:41] again with fixed action patterns, [15:44] including swinging of the limbs, right? [15:46] Punching. [15:47] This wouldn't necessarily be controlled [15:49] punching, [15:50] but also biting behavior. So, it's [15:52] remarkable to me at least that we have [15:54] circuits in our brain that can evoke [15:57] violent use of things like our mouth or [15:59] violent use of things like our limbs. [16:01] That of course could be used for things [16:03] like singing or kissing or eating or [16:07] you know, gesticulating in any kind of [16:09] polite or impolite way. The point here [16:12] is that neural circuits, not individual [16:14] brain areas, evoke the constellation of [16:17] behaviors that we call aggression. Now, [16:19] many of you are probably puzzled, or at [16:20] least should be, [16:22] because I've been talking about this [16:24] highly specialized brain area, the [16:25] ventromedial hypothalamus, and this [16:27] highly specialized subcategory of [16:29] neurons in the ventromedial [16:31] hypothalamus, these neurons that make [16:32] estrogen receptor. [16:34] And yet, the activation of those cells [16:37] triggers dramatic and immediate [16:39] aggression both in males and in females, [16:42] and both against males and against [16:44] females. So, what's going on here? Most [16:46] of us think about estrogen and we don't [16:49] immediately think of aggression. Most of [16:51] us hear testosterone and we might think [16:53] about aggression. To make a long story [16:54] short, [16:56] and to dispel a still unfortunately very [16:59] common myth, testosterone does not [17:02] increase aggressiveness. [17:04] Testosterone increases proactivity and [17:07] the willingness to lean into effort in [17:10] competitive scenarios. If people are [17:12] given testosterone, or if you look at [17:15] people who have different [17:17] levels, excuse me, of testosterone [17:19] endogenously that they naturally make. [17:21] What you'll find is that testosterone [17:23] tends to increase competitiveness, but [17:26] not just in aggressive scenarios. So, if [17:29] somebody is already aggressive, giving [17:31] them testosterone will have the tendency [17:34] to make them more aggressive. If [17:35] somebody, however, is very benevolent [17:37] and altruistic, giving them testosterone [17:39] will make them more benevolent and [17:41] altruistic, at least up to a point. [17:42] Turns out there's evidence that in [17:45] certain context, estrogen can make [17:47] people more aggressive. So, what's going [17:48] on here? [17:50] Well, what's going on is that [17:52] testosterone can be converted into [17:55] estrogen through a process called [17:57] aromatization. There's an enzyme called [17:59] aromatase. Anytime you have word that [18:01] ends in ASE, at least if it's in the [18:03] context of biology, it's almost always, [18:06] not always, but almost always an enzyme. [18:08] So, the aromatase enzyme converts [18:11] testosterone into estrogen. And it is [18:13] actually testosterone aromatized, [18:16] converted into estrogen, and then [18:19] binding to these estrogen-containing [18:22] neurons in the ventromedial hypothalamus [18:24] that triggers aggression. [18:26] I want to repeat that. It is not [18:28] testosterone itself that triggers [18:29] aggression. It is testosterone [18:31] aromatized into estrogen within the [18:33] brain and binding to these estrogen [18:36] receptor-containing neurons in the [18:37] ventromedial hypothalamus that evokes [18:39] aggression, and dramatic aggression at [18:42] that. Now, this effect of estrogen [18:44] causing aggression in the brain [18:46] is very robust, so much so that if you [18:49] take a mouse that lacks the aromatase [18:51] enzyme, or a human that lacks the [18:53] aromatase enzyme, and they do exist, [18:56] then [18:57] there is a reduction in overall [18:58] aggression [19:00] despite high levels of testosterone. It [19:02] doesn't matter how much you increase [19:04] testosterone or any of its other [19:06] derivatives, you do not observe this [19:09] aggression. This runs counter to [19:10] everything that we know and think about [19:12] the role of testosterone. So, the next [19:14] time somebody says testosterone makes [19:16] people aggressive, you can say, "Ah, no, [19:18] actually, it's estrogen that makes [19:21] people aggressive, and animals [19:22] aggressive for that matter." Now, of [19:24] course, it is the case that because [19:27] males have relatively less estrogen [19:30] circulating in their brain and body than [19:32] females, right? Because they have [19:34] testes, not ovaries, that testosterone [19:37] is required in the first place in order [19:39] to be converted into estrogen to [19:41] activate this aggressive circuit [19:42] involving these estrogen [19:44] receptor-containing neurons in the [19:45] ventromedial hypothalamus. So, we've [19:47] established that it's not testosterone, [19:49] but testosterone converted into estrogen [19:52] that activates these circuits for [19:54] aggression. Nonetheless, it's still [19:56] surprising, right? I mean, most of us [19:57] don't think about a estrogen as the [19:59] hormone that stimulates aggression. But, [20:02] it turns out it's all contextual. There [20:04] are beautiful data showing that whether [20:06] or not estrogen stimulates aggression [20:08] can be [20:09] powerfully modulated by whether or not [20:12] days are short or days are long. In [20:14] other words, whether or not there's a [20:15] lot of sunshine or not. Day length [20:19] is converted into hormonal signals and [20:21] chemical signals, and the primary [20:22] hormonal and chemical signals involve [20:25] melatonin [20:26] and dopamine, and also the stress [20:28] hormones. So, to make a very long story [20:29] short, in the long days where we get a [20:31] lot of sunlight, both, you know, eyes [20:33] and on our skin, melatonin levels are [20:35] reduced. Melatonin is a hormone that [20:36] tends to produce states of sleepiness [20:39] and quiescence. It also tends to [20:41] activate pathways that tend to reduce uh [20:43] things like breeding and sexual [20:45] behavior. [20:46] In long days, dopamine is increased. [20:49] Dopamine is a molecule associated with [20:50] feelings of well-being and motivation, [20:53] and the desire to seek out all sorts of [20:56] things. And in long days, [20:58] provided we're getting enough sunlight [21:00] on our skin and to our eyes, [21:03] the stress hormones, especially cortisol [21:05] and some of the other stress hormones [21:07] are reduced in levels. If estrogen [21:08] levels are increased experimentally [21:11] under long-day conditions, [21:14] it does not evoke aggression. However, [21:16] in short days, if estrogen is increased, [21:19] there's a heightened predisposition for [21:21] aggression. [21:22] And that makes perfect sense if you [21:25] think about what short days do to the [21:27] biology of your brain and body. The [21:29] melatonin signal goes up. There's more [21:31] melatonin circulating for more of each [21:32] 24-hour cycle. Stress hormones are [21:35] circulating more. Why? Short days tend [21:37] to be associated with winter. In winter, [21:40] we are bombarded with more bacteria and [21:42] viruses because bacteria and viruses [21:44] actually survive better in cold than [21:47] they do in heat. So, shorter days are [21:49] conducive to aggression not because days [21:52] are short per se, but because stress [21:55] hormone levels are higher and [21:57] because dopamine levels are lower. Now, [22:00] here's where all of this starts to [22:01] converge on a very clear biological [22:03] picture, a very clear psychological [22:05] picture, and indeed a very clear set of [22:07] tools that we can think about and use. [22:10] Under conditions where cortisol is high, [22:12] where the stress hormone is elevated, [22:15] and under conditions where the [22:16] neuromodulator serotonin is reduced, [22:20] there is a greater propensity for [22:22] estrogen to trigger aggression. For [22:24] males who make a lot of testosterone [22:26] relative to estrogen, [22:27] you have to swap in your mind this idea [22:29] that if testosterone is high, that means [22:32] that estrogen is low because if [22:33] testosterone is high, there is going to [22:36] be some aromatization, that conversion [22:38] of testosterone to estrogen. So, anytime [22:40] you hear that testosterone is high, you [22:42] should think testosterone is high in the [22:44] body and perhaps estrogen is low in the [22:45] body, but that means that there's going [22:46] to be heightened levels of estrogen in [22:48] the brain, and therefore increased [22:51] propensity for aggression. In females [22:53] who generally make less testosterone [22:55] relative to estrogen, there is [22:57] sufficient estrogen already present to [22:59] trigger aggression. So, [23:01] both males and females are primed for [23:04] aggression, but that's riding on a [23:06] context, [23:08] and that context of whether or not you [23:10] get a tendency for aggression or not [23:13] depends on whether or not cortisol is [23:14] high or low, and I'm telling you that if [23:16] cortisol is relatively higher in any [23:19] individual, there's going to be a tilt, [23:21] an increase in that hydraulic pressure [23:24] that Lorenz talked about toward [23:26] aggression. [23:28] And [23:29] if [23:30] serotonin, the neuromodulator that's [23:32] associated with feelings of well-being [23:35] and sometimes even of slight passivity, [23:37] but certainly of well-being, [23:39] if serotonin is low, there's also going [23:41] to be a further shift towards an [23:43] aggressive tendency. So, if we return to [23:46] Lorenz's hydraulic pressure model of [23:49] aggression and other internal states, [23:52] we realize that [23:53] external stimuli, things that we hear, [23:55] things that we see, for instance, [23:57] someone saying something upsetting or us [23:59] seeing somebody do something that we [24:02] don't like to others or to us, [24:05] as well as our internal state, our [24:08] subjective feelings of well-being, but [24:10] also our stress level, our feelings of [24:12] whether or not we have enough resources [24:14] and are content with what we have, all [24:16] of that is converging on this thing that [24:18] we call internal state and creating this [24:19] pressure of either to be more aggressive [24:21] or less aggressive. Now, we have some [24:23] major players feeding into that final [24:26] pathway, that question of whether or not [24:28] will we hit the other person? Will we [24:30] say the thing that is considered [24:32] aggressive? Will we not say it? Again, [24:35] there are many things funneling into [24:36] that question and dictating whether or [24:38] not the answer is absolutely I'll fight [24:40] back or I'm going to attack them even [24:42] unprovoked. We really can boil them down [24:44] to just a few common elements, and I'm [24:46] telling you that those elements are [24:48] whether or not cortisol levels are [24:49] relatively lower [24:51] or relatively higher. Again, relatively [24:53] higher is going to tend to make people [24:55] more reactive. Why? Because [24:58] reactivity is really a function of the [25:00] autonomic nervous system, which is sort [25:02] of like a seesaw that oscillates between [25:05] the so-called sympathetic [25:07] arm of the autonomic nervous system, [25:08] which tends to put us into a state of [25:10] readiness through the release of [25:11] adrenaline. Cortisol and adrenaline, [25:13] when they're circulating in the brain [25:14] and body, make us more likely to move [25:16] and to react and to speak. It's actually [25:18] what will induce a kind of low-level [25:20] tremor, which is an anticipatory tremor [25:22] to be able to move more quickly, right? [25:24] A body in motion is more easily set into [25:26] further motion, that is. And in terms of [25:28] keeping cortisol in a range that's [25:30] healthy and doesn't bias someone toward [25:33] high levels of aggression and [25:34] irritability, that's again going to be [25:37] set by a number of [25:39] larger modulators or contextual cues. [25:41] And I've talked about some of those on [25:42] the podcast, but I'll just briefly recap [25:43] them now. Obviously, getting sunlight in [25:47] your eyes early in the day and as much [25:48] sunlight as you safely can in your eyes [25:51] throughout the day is going to be [25:52] important again because of this effect [25:55] of estrogen in long days not increasing [25:58] aggression. However, in shorter days [26:01] estrogen increases aggression because of [26:03] the increase in cortisol observed in [26:05] short days. Another way to reduce [26:07] cortisol [26:08] was discussed in our episode on heat and [26:10] the use of sauna and heat, but also hot [26:13] baths. It turns out that hot baths and [26:15] sauna [26:16] can be very beneficial for reducing [26:17] cortisol. All the details on that are [26:19] included in the episode on heat and it's [26:20] time-stamped, so you can go directly to [26:22] that if you want to learn about the [26:23] temperatures and the various durations, [26:25] but to just give a uh [26:27] a synopsis of that, a 20-minute [26:30] sauna at anywhere from 80 to 100° C [26:34] is going to be beneficial for reducing [26:36] cortisol. If you don't have access to a [26:38] sauna, you could do a hot bath. And of [26:40] course, some of you may be interested in [26:41] exploring the supplementation route. And [26:43] for reductions in cortisol, really the [26:46] uh chief player there is ashwagandha, [26:49] which is known to decrease cortisol [26:51] fairly potently. I should just warn you [26:53] that if you're going to use ashwagandha [26:55] in order to reduce cortisol, first of [26:57] all, check with your doctor or health [26:58] care provider before adding or [27:00] subtracting anything from your [27:01] supplementation or health regimen. Of [27:03] course, I don't just say that to protect [27:04] us. I say that to protect you. You are [27:06] responsible for your health, what you [27:07] take and what you don't take. Chronic [27:09] supplementation with ashwagandha can [27:11] have some not so great effects of [27:13] disruption of other hormone pathways and [27:15] neurotransmitter pathways. So, the limit [27:18] seems to be about 2 weeks of of regular [27:20] use before you'd want to take a break of [27:21] about 2 weeks. So, ashwagandha, again, a [27:24] very potent inhibitor of cortisol, but [27:27] with some other effects as well. [27:29] Don't use it chronically for longer than [27:30] 2 weeks. But, if your goal is to reduce [27:32] cortisol, let's say you're going through [27:34] a period of increased irritability and [27:36] aggressive tendency, maybe you're also [27:38] not getting as much light as you would [27:39] like, and perhaps also if there are [27:42] other um circumstantial things leading [27:44] you towards more aggressiveness and your [27:45] goal is to reduce aggressiveness, that [27:47] can be potentially helpful. And in light [27:49] of all this stuff about cortisol and [27:52] estrogen and day length, [27:54] I should mention that there are, in [27:56] fact, some people who have a genetic [27:58] predisposition to be more irritable and [28:02] aggressive. There is a genetic variant [28:06] present in certain people that adjust [28:09] their estrogen receptor sensitivity. [28:12] And that estrogen receptor sensitivity [28:15] can result in increased levels of [28:17] aggression. [28:18] Sometimes dramatic increases. However, [28:21] and also very interestingly, [28:23] photoperiod, meaning day length, [28:26] is a strong modulator of whether or not [28:29] that aggressiveness turns up or not. [28:31] Whether or not that person with the [28:33] particular gene variant is more [28:35] aggressive or not depends on how long [28:38] the day is and how long the night is. [28:40] One particular study that I like that [28:42] references this is Trainor et al. The [28:45] title of the study is photoperiod [28:46] reverses the effects of estrogens on [28:48] male aggression via genomic and [28:50] non-genomic pathways. This was a paper [28:52] published in the Proceedings of the [28:53] National Academy of Sciences. It really [28:55] points to the fact that rarely is it the [28:57] case that just one gene will cause [29:00] somebody to be hyper-aggressive. [29:03] Almost always there's going to be an [29:05] interplay between genetics and [29:06] environment and as environment changes [29:09] such as day length changes and the [29:10] length of night changes, so too will the [29:12] tendency for people with a given genetic [29:15] variant to be more aggressive or not. [29:17] Now of course in the absence of detailed [29:19] genetic testing for this particular [29:21] estrogen receptor variant, most people [29:23] I'm guessing you are probably not [29:25] walking around knowing that you have [29:26] this gene or not. [29:29] Regardless, I think it's important to [29:31] pay attention to how you feel at [29:33] different times of year depending on [29:35] whether or not summer, whether or not [29:36] it's winter, whether or not you're [29:37] getting sufficient sunlight, [29:39] meaning viewing sufficient sunlight or [29:41] not, whether or not you're getting [29:42] sufficient sunlight exposure to your [29:43] skin or not, whether or not you're [29:45] indoors all the time. Generally those [29:46] things correlate with season, but not [29:50] always. You can go through long bouts of [29:52] you know hard work in the summer months [29:54] when days are long but you're indoors a [29:55] lot and getting a lot of fluorescent [29:57] light exposure late in the evening and [29:58] perhaps that's when you're feeling more [30:00] aggressive. So we have to be careful [30:01] about drawing a one-to-one relationship [30:04] between any biological feature and [30:06] certainly psychological or behavioral [30:07] feature like aggressiveness, but it's [30:10] I believe helpful to know that these [30:12] genetic biases exist, how they play out. [30:15] Again, they shift our biology in in a [30:17] general thematic direction. They don't [30:20] change one thing, they change a variety [30:21] of things that bias us toward or away [30:23] from certain psychological and [30:25] behavioral outcomes and [30:27] the various things that we can do in [30:29] order to offset them. We described those [30:31] earlier in terms of trying to keep [30:32] cortisol low by getting sufficient [30:34] sunlight regardless of time of year and [30:36] regardless of whether or not you happen [30:38] to have this particular genetic variant. [30:39] I I to share with you a study that's [30:41] focused on kids, but that has [30:44] important ramifications for adults as [30:46] well. There are many kids out there that [30:48] suffer from so-called attention deficit [30:50] hyperactivity disorder, ADHD. There are [30:53] also many adults we are finding that are [30:54] suffering from ADHD. In any event, [30:57] the study I'm about to share with you [30:58] explored how our particular pattern of [31:00] supplementation in kids with ADHD was [31:04] able to reduce [31:05] aggressive episodes and impulsivity and [31:08] increase self-regulation. [31:10] And the title of the study is efficacy [31:12] of carnitine in the treatment of [31:13] children with attention deficit [31:15] hyperactivity disorder. [31:16] Even though they put carnitine in the [31:17] title, that what they focused on was [31:20] whether or not acetyl-L-carnitine [31:22] supplementation could somehow adjust the [31:25] behavioral tendency of these kids with [31:26] ADHD. And to make a long story short, [31:29] indeed it did. There was a very [31:31] significant effect of acetyl-carnitine [31:33] supplementation on improving some of the [31:35] symptomatology symptomatology, excuse [31:38] me, of ADHD. This was a randomized [31:40] double-blind placebo-controlled [31:41] double-crossover study. They showed [31:43] significant reductions in their [31:45] so-called total problem score. The total [31:47] problem score is a well-established [31:48] measure of behavioral problems in kids [31:51] with ADHD and, I should say, adults with [31:54] ADHD. Reductions in attentional problems [31:56] overall, reductions in delinquency, and [31:59] most important for the sake of today's [32:00] discussion, significant reductions in [32:02] aggressive behavior. They were able to [32:04] confirm the shifts in L-carnitine [32:08] within the bloodstream of these kids. [32:09] That is, they were able to correlate the [32:11] physiology with the psychological [32:12] changes. So, studies such as this, I [32:15] think, are useful because they point to [32:17] the fact that [32:19] very seldom, if ever, will there be one [32:21] supplement or one nutritional change or [32:24] even one behavioral change that's going [32:26] to completely shift an individual from [32:28] being aggressive and impulsive, but [32:30] rather that by combining different [32:33] behavioral regimens, by paying attention [32:35] to things like time of year and work [32:37] conditions and school conditions and [32:39] overall levels of stress and likely [32:42] therefore levels of cortisol etc. [32:44] that you can use behaviors, diet and [32:47] supplementation as a way to shift that [32:49] overall internal milieu from one of [32:52] providing a lot of internal hydraulic [32:54] pressure as it's been called throughout [32:56] the episode toward aggressive [32:58] impulsivity and relax some of that [33:00] hydraulic pressure and reduce aggressive [33:03] tendencies. Thank you for joining me for [33:05] our discussion about the biology, [33:07] psychology and actionable tools around [33:10] aggression and as always thank you for [33:12] your interest in science.