Love and Hate in the Brain

Summary: Activity in the medial preoptic area tilts the mouse brain toward love and affection, while activity in the ventromedial hypothalamus is associated with more aggressive or hateful acts.

Source: CalTech

Mounting behavior, that awkward thrusting motion dogs sometimes do against your leg, is usually associated with sexual arousal in animals, but this is not always the case. New research by Caltech neuroscientists that explores the motivations behind mounting behavior in mice finds that sometimes there is a thin line between love and hate (or anger) in the mouse brain.

The research, which appears in the journal Nature, was conducted in the lab of David Anderson, the Seymour Benzer Professor of Biology, Tianqiao and Chrissy Chen Institute for Neuroscience Leadership Chair, investigator with the Howard Hughes Medical Institute, and director of the Tianqiao and Chrissy Chen Institute for Neuroscience.

“Our lab is interested in understanding how social behaviors and underlying emotional states are controlled by the brain,” explains lead author Tomomi Karigo, a postdoctoral scholar at Caltech. “While we were studying social behaviors in mice, we sometimes noticed that male mice would mount other males, in a way similar to how they would mount females,” Karigo says.

It was unclear whether these male mice tried to mate with a male because they simply mistook it for a female or if they knew it was a male but intended to establish dominance over it. The researchers hoped to understand whether a male mouse mounting another male mouse reflects a different intent than a mouse mounting a female mouse, and how mounting behavior is regulated in the brain.

To find out, the researchers first recorded videos of males mounting both male and female mice. Using machine learning, a type of software that learns and adapts through experience, they analyzed the videos to see whether there was anything different in the mounting behavior that was exhibited toward a male versus that toward a female mouse. The machine-learning analysis revealed no obvious difference in the mechanics of the mounting behavior.

The researchers then looked for other clues in the mounting males’ behavior that might differentiate female-focused versus male-focused mounting.

One clue was that male mice appear to “sing” to females while mating with them. These songs, known as ultrasonic vocalizations, are too high-pitched for humans to hear, but can be picked up with a special microphone. Karigo and the team found that mounting mice sing only to female mice, not to males. In addition, when a male is mounting another male, the two animals usually end up fighting after a short period of mounting. This does not happen in the case of a female mounting partner.

These results suggested that mounting behavior toward a female has a different meaning than mounting behavior toward a male. Specifically, mounting toward a male is probably the expression of dominance or mild anger (aggressive mounting) and not a reproductive (or so-called affiliative) behavior.

Next, the researchers explored which brain regions are responsible for each type of mounting behavior.

When a male mouse mounted male or female mice, the researchers observed neural activity in an area of its brain called the hypothalamus, which controls, among other things, hunger, thirst, metabolism, and defensive behaviors. In particular, two regions of the hypothalamus seemed to be involved: the medial preoptic area (MPOA) and the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl). The MPOA showed high levels of activity when the male mouse was mounting, and singing to, a female; conversely, the VMHvl showed high levels of activity when the male mouse was mounting, but not singing to, a male.

The team then took a closer look at the activity of individual neurons in the MPOA and VMHvl. They found that distinct groups of neurons were activated during reproductive mounting and aggressive mounting, in each brain region. In addition, the researchers discovered that they could train a computer to correctly predict whether the mounting was sexual or aggressive, based purely on the pattern of neuronal activity in these two regions.

The researchers then tested to see if those brain regions actually controlled the two mounting behaviors, or if activity in the regions was simply correlated with the behaviors. They did this using a technique called optogenetic stimulation, in which light is used to trigger the firing of neurons. By directing the light to specific areas of the brain, researchers can induce neuronal activity there, and thus induce behaviors.

This shows a heart with prison bars and a brain behind it
The researchers then looked for other clues in the mounting males’ behavior that might differentiate female-focused versus male-focused mounting. Image is in the public domain

When the researchers presented a female mouse to a male mouse, the male mouse began to sing and mate with a female. But when the researchers stimulated the male’s VMHvl, the male stopped singing and started to show aggressive mounting behavior toward the female. Conversely, if a male mouse was engaging in aggressive behaviors toward another male and the researchers stimulated its MPOA, the aggressive mouse would stop fighting, begin to sing, and attempt to mate with the other male.

Karigo and Anderson liken this to a seesaw of love and hate. Activity in the MPOA tilts the seesaw toward love, while activity in the VMHvl tilts it toward hate (or aggression).

“In this study, we used mounting behavior as an entry point to understand the underlying neural mechanisms that control emotional or motivational states,” Karigo says. She says their findings advance our understanding of how the mouse brain, and more broadly the mammalian brain, works to control emotions, and she adds that they may one day help us to better understand human behaviors.

The paper describing their findings, titled, “Distinct hypothalamic control of same- and opposite-sex mounting behaviour in mice,” was published online by Nature on December 2. Co-authors are Ann Kennedy, formerly of Caltech and now at the Feinberg School of Medicine at Northwestern University; neurobiology graduate students Bin Yang and Mengyu Liu of Caltech; Derek Tai, formerly a research assistant at Caltech and now at the Touro University Nevada College of Osteopathic Medicine; Iman A. Wahle (BS ’20), a Schmidt Scholar at Caltech; and David J. Anderson.

Funding: Funding for the research was provided by the National Institutes of Health, the Simons Collaboration on the Global Brain Foundation, the Howard Hughes Medical Institute and the Tianqiao and Chrissy Chen Institute for Neuroscience, of which Anderson is the director.

About this neuroscience research news

Source: CalTech
Contact: Emily Velasco – CalTech
Image: The image is in the public domain

Original Research: Closed access.
Distinct hypothalamic control of same- and opposite-sex mounting behaviour in mice” by Tomomi Karigo, Ann Kennedy, Bin Yang, Mengyu Liu, Derek Tai, Iman A. Wahle & David J. Anderson. Nature


Distinct hypothalamic control of same- and opposite-sex mounting behaviour in mice

Animal behaviours that are superficially similar can express different intents in different contexts, but how this flexibility is achieved at the level of neural circuits is not understood. For example, males of many species can exhibit mounting behaviour towards same- or opposite-sex conspecifics, but it is unclear whether the intent and neural encoding of these behaviours are similar or different. Here we show that female- and male-directed mounting in male laboratory mice are distinguishable by the presence or absence of ultrasonic vocalizations (USVs), respectively. These and additional behavioural data suggest that most male-directed mounting is aggressive, although in rare cases it can be sexual. We investigated whether USV+ and USV mounting use the same or distinct hypothalamic neural substrates. Micro-endoscopic imaging of neurons positive for oestrogen receptor 1 (ESR1) in either the medial preoptic area (MPOA) or the ventromedial hypothalamus, ventrolateral subdivision (VMHvl) revealed distinct patterns of neuronal activity during USV+ and USV mounting, and the type of mounting could be decoded from population activity in either region. Intersectional optogenetic stimulation of MPOA neurons that express ESR1 and vesicular GABA transporter (VGAT) (MPOAESR1∩VGAT neurons) robustly promoted USV+ mounting, and converted male-directed attack to mounting with USVs. By contrast, stimulation of VMHvl neurons that express ESR1 (VMHvlESR1 neurons) promoted USV mounting, and inhibited the USVs evoked by female urine. Terminal stimulation experiments suggest that these complementary inhibitory effects are mediated by reciprocal projections between the MPOA and VMHvl. Together, these data identify a hypothalamic subpopulation that is genetically enriched for neurons that causally induce a male reproductive behavioural state, and indicate that reproductive and aggressive states are represented by distinct population codes distributed between MPOAESR1 and VMHvlESR1neurons, respectively. Thus, similar behaviours that express different internal states are encoded by distinct hypothalamic neuronal populations.

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