Summary: New research has revealed that adult mice’s brains are encoded by the same neural mechanisms that govern aggression and sexual intimacy. The research found that a certain type of neural message, called a line object, represents the strength and boldness of these emotional says.
In the case of anger, this signal accumulates over time and gradually declines as the stimulus is removed, similar to how people calm down after being angry. The results suggest that different sensations does share common neural pathways, probably offering insights into mental health treatments.
Important Information
- Aggression and intimacy in animals are both encoded by a neurological “line attractor”.
- Similar to human psychological says, these signs accumulate and continue to do so over time.
- Results does tell potential treatments for emotional and mental health problems.
Origin: CalTech
A series of three documents from researcher David J. Anderson’s experiment, two in the journal , Nature , and one in the journal , Cell, reveal new insights into the neurological signals underlying internal mental states including anger and sexual intimacy.
The findings of the studies demonstrate that a typical sort of transmission in the brain is responsible for both the state of aggression in female animals and the state of arousal in adult mice.
These studies are the result of partnerships within the team of Anderson, who is the Seymour Benzer Professor of Biology, Howard Hughes Medical Institute Investigator, Tianqiao and Chrissy Chen Leadership Chair, and chairman of the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.
The three fresh reports all expand on earlier research from the Anderson test, particularly a study led by Computation and Neural Systems grad student Aditya Nair and former postdoctoral researcher Ann Kennedy, who is now an associate professor at the Scripps Research Institute, next year.
In that study, researchers discovered , a neural signal encoding the persistence and intensity of an internal state of aggression. Nair, who is also a co-first author on the two most recent papers, Nature , and second author on the most recent paper, Cell , used machine learning to model brain activity, which revealed that mice’s line attractor was the neural signal that caused the state of aggression.
A line attractor is a specific pattern of activity, created by the interconnections between brain cells, that follows the shape of a valley. The energy in a line attractor system tends to flow down the valley, like a ball rolling down into a trough, in a graph showing the energy moving between neurons over time. Once neural energy has reached the bottom, it tends to stay there and flow along a line, like a river moving along the bottom of a valley.
The further along the line, the more aggressive the animal becomes, the more the attractor signal encoding aggression increases. Then after a fight, it takes time for the neural energy to flow back out of the valley. According to the researchers, this gradual decline might be related to how long it takes for someone to calm down when they are extremely upset or angry.
Nair says this finding was unexpected because, while line attractors had been observed in the cortex and hippocampus ( which are evolutionarily recent brain regions that control higher cognitive functions ), many had assumed that the hypothalamus ( an evolutionarily ancient region that controls instinctive behaviors ) would not possess these types of signals.
Nair notes that the next challenge was to” truly test our theory and see if this signal was indeed a property of the brain networks we were directly observing, to understand what mechanisms support this network, and to ask if this was specific to aggression or if it reflected a common principle for the brain to represent emotion states.”
Because the original study was based on machine learning modeling, the researchers did not yet have evidence that the signal of escalating aggressiveness was encoded by local neural circuits.
It was possible that the line attractor signal was being produced in another brain region and passed along to the hypothalamus via long-range connections while the researchers were observing activity in a particular region of the hypothalamus.
To answer that question, postdoctoral scholar Amit Vinograd and Nair performed a technically challenging “record and play back” type of experiment designed to test whether the neural signal could be reproduced in a laboratory setting by reactivating the right cells in mice brains.
This required the researchers to use advanced techniques to monitor neural activity in the hypothalamus in real-time while a mouse was aggressive, identify which neurons were involved in the aggressiveness line attractor, restimulate those specific neurons, and then try to reproduce the line attractor.
In other words, if an external stimulus caused the neural energy to flow into the valley, would directly stimulating the observed neurons push the system into the same valley as well? If so, it would indicate that the line attractor was not passively “inherited” from some other brain region and could have been locally produced by the neurons being observed.
” This experiment was one of those rare’ movie moments ‘ you do n’t get often in science and, to me, really showed the power of collaboration”, Nair says.
The researchers created a hologram of the specific neurons they needed to activate while using machine learning to model the neural data and determine the line attractor in the brain. Then, they used a laser to reactivate those neurons.
When the researchers artificially reactivated the individual neurons that made up the line attractor signal, they observed that the cells “integrated” the activation inputs, gradually accumulating them into a stronger, more persistent signal, the line attractor signal.
This accumulation could be compared to more water flowing into a river and pushing the river farther along the bottom of a valley.
We became curious about how the signal was being created once we realized that it was actually intrinsic to the network.
” So, then we did experiments to test the functional connectivity of neurons by activating single cells to see whether other cells in the network also light up. We observed what we refer to as “recurrent connectivity,” which refers to the interconnection of a particular cell population and the line attractor.
” This interconnectivity allows them to do this computation that integrates the information, the strength of connectivity increases because the cells are amplifying each other.”
The tendency for the energy to enter the line attractor shape is caused by this amplification. The study marked the first direct experimental evidence of line attractor dynamics in a mammalian brain—something that was previously only theorized to exist.
The results are described in the paper” Causal evidence of a line attractor encoding an affective state,” which was published in Nature.
In another study published in , Cell,  , researchers in the Anderson lab, led by postdoctoral scholar George Mountoufaris, found that the neuropeptides oxytocin and vasopressin—brain chemicals important in social behavior and social learning—are necessary for the aggressiveness line attractor to form.
The researchers reaffirmed previous hypotheses made by previous lab research by positing that the aggressiveness signal, which lasts for a while longer than other brain signals, is carried out in neural circuits by slow-acting chemical messengers like neuropeptides.
While many neural signals are implemented with the more common and fast-acting chemical messenger glutamate, neuropeptides like oxytocin and vasopressin can influence the activity of neural circuits with longer-lasting and wider-reaching effects in the brain.
CRISPRoscopy, a new method that combines the gene-editing technology , CRISPR, with single-cell calcium imaging methods to record brain activity, was created to investigate the role of these neuropeptides in implementing the signal of aggressiveness.
Using the technique, researchers disrupted specific neurons ‘ ability to detect oxytocin and vasopressin. The results of this genetic disruption were then examined for both the animals ‘ social and brain activity.
” While aggression was not completely abolished, the animals exhibited reduced aggression and fought with less vigor,” Mountoufaris says”. The mice were unable to maintain the rage state required to escalate the aggression without the signaling of oxytocin and vasopressin.
Inside the brain, the disruption affected how long individual neurons, as well as populations of neurons, remained active once triggered by an aggression-promoting stimulus.
According to Mountoufaris,” The persistence of neural responses at the single-cell level was significantly decreased.” And the population-level activity was completely compromised.”
These findings demonstrated that the neuropeptide signaling did not cause the line attractor to form without them. This suggests that oxytocin and vasopressin are essential components of the aggressiveness signal’s implementation.
Mountoufaris says this result was surprising and significant because most previous theoretical studies had discounted the role of such slow chemical messengers in generating line attractors.
The full study, published in Cell.,” A line attractor encoding a persistent internal state requires neuropeptide signaling.
While the hypothalamus in male mice has a line attractor encoding a signal of anger, a new study led by graduate alum Mengyu Liu ( PhD ‘ 24 ) and Nair found that the same region in female mice has a line attractor encoding sexual receptivity, which may generate an internal state of sexual arousal.
Researchers led by Liu and conducted a previous , study   that found a female-specific type of neuron within the hypothalamus that promoted sexual receptivity. Surprisingly, however, as females proceeded through their estrus cycle ( which in mice lasts about a week ), there was no change in the overall level of activity of these neurons whether the females were in their receptive or non-receptive phase.
Nair used the same machine learning methods to analyze the female mouse data to better understand the sexual receptivity-promoting cell population’s activity.
” We think of sexual arousal as an internal state, which has the same qualities as an aggressive state: persistence and intensity,” Nair says”. This gave us the opportunity to examine whether the line attractor we observed in aggression was unique to that state or if it was a typical form of brain processing used for various emotion states, including sexual arousal.
This approach indeed revealed a line attractor encoding the signal of sexual receptivity in females. In response to repeated sexual contact by male mice during the “receptive” stages of the estrus cycle, the arousal signal moved along the valley’s bottom.
As male mice sniffed, mounted, and mated with female mice, the female mouse brains accumulated those inputs, and they were more likely to display receptive behavior in response to males.
According to Liu,” One surprising discovery is the gradual ramping up of sexual arousal in females during mating, which can take several minutes or even longer.”
The authors speculate that this ramping and persistent neural activity ( which flows in a similar pattern to the aggressiveness signal in males ) may serve to keep the females” interested “in the male in between bouts of mounting, which are intermittent and sporadic.
Additionally, the study found that the females ‘ sexual receptivity to the mating line attractor only increased during particular estrus cycles. If females were mounted by males during the non-receptive phase of their cycle, the line attractor was not observed.
We discovered that being in the appropriate hormonal state is essential for achieving this heightened state of arousal, says Liu.
” Without the right hormonal conditions, even repeated successful copulations—essentially nonconsensual encounters—may not lead to sexual arousal in the female.”
According to Liu,” Historically, scientific research has disproportionately focused on males, leaving largely unexplored female-specific biological questions,”
” There are significant differences between the sexes in physiology and brain function, which limit women’s ability to fully benefit from male-centered scientific findings. It is crucial to advance gender-inclusive science and enhance women’s health by putting gender-inclusive topics and questions at the forefront.
Liu says the findings of the study can ultimately guide research to inform health care providers and the public about the natural fluctuations in a woman’s emotional state during sexual experiences due to hormonal changes and may also provide justification for the development of hormone therapies aimed at improving sexual health in women.
The study is titled” A hypothalamic line attractor encoding female mating dynamics” and was published in Nature.
The three new studies reveal unique findings about how internal states of male aggressiveness and female sexual receptivity are implemented in the brain. These internal states, according to the authors, are likely present in people as well, where we may subconsciously associate them with feelings like “angry” and” sexual arousal,” respectively.
Altogether, the studies suggest that the persistence and intensity of emotional states might be encoded by a common property of certain neural networks in the brain in the form of line attractors.
It has been hypothesized that attractors may be responsible for some types of long-lasting mental illness, such as depression, because they are stable states of brain activity that are difficult to dispel once they form.
” We’re very excited about what these findings could mean for mental health conditions,” Nair says”. Utilizing cutting-edge tools, these studies combine cutting-edge tools that can reveal how attractors might react to various disorders and how we might be able to use intervention techniques for mental health therapies.
” These studies have opened up a new era of work in my laboratory using computational approaches,” says Anderson. Although these methods are a keystay of research at Caltech in other disciplines, Anderson had not previously applied them to his own work.
” In the best tradition of Caltech,” Anderson says”, it was the expertise of a graduate student that brought this new approach to our research, with very exciting results and implications.”
Funding:
The BRAIN Initiative, the Howard Hughes Medical Institute, and the Agency for Science, Technology, and Research of Singapore ( A*STAR ) provided funding for this research.
About this aggression, arousal, and neuroscience research news
Author: David J. Anderson
Source: CalTech
Contact: David J. Anderson – CalTech
Image: The image is credited to Neuroscience News
Original research: Free of charge.
” Causal evidence of a line attractor encoding an affective state” by David J. Anderson et al. Nature
Open access.
By David J. Anderson and colleagues,” A hypothalamic line attractor encoding female mating dynamics.” Nature
Open access.
By David J. Anderson and al.,” A line attractor encoding a persistent internal state requires neuropeptide signaling.” Cell
Abstract
Causal evidence of a line attractor encoding an affective state
Continuous attractors are an emergent property of neural population dynamics that have been hypothesized to encode continuous variables such as head direction and eye position.
The difficulty of limiting perturbations to specific neurons within contributing ensembles has hampered the ability to directly demonstrate the neural implementation of a continuous attractor in mammals. Dynamical systems modelling has revealed that neurons in the hypothalamus exhibit approximate line-attractor dynamics in male mice during aggressive encounters.
We have previously suggested that these dynamics may account for the variation in the intensity and persistence of an aggressive internal state. Here we report that these neurons also showed line-attractor dynamics in head-fixed mice observing aggression. Using two-photon calcium imaging and holographic optogenetic perturbations, we were able to identify and manipulate line-attractor-contributing neurons.
On-manifold perturbations yielded integration of optogenetic stimulation pulses and persistent activity that drove the system along the line attractor, while transient off-manifold perturbations were followed by rapid relaxation back into the attractor. Additionally, single-cell stimulation and imaging revealed a selective functional connectivity among the attractor-contributing neurons.
Notably, individual differences among mice in line-attractor stability were correlated with the degree of functional connectivity among attractor-contributing neurons. Our empirical findings are best summarized in mathematical recurrent neural network modeling, which showed that dense subnetwork connectivity and slow neurotransmission.
Our work bridges circuit and manifold levels, providing causal evidence of continuous attractor dynamics encoding an affective internal state in the mammalian hypothalamus.
Abstract
A hypothalamic line attractor encoding female mating dynamics
Females exhibit complex, dynamic behaviours during mating with variable sexual receptivity depending on hormonal status. However, it is still largely unknown how their brains encoding the dynamics of mating and receptivity are encoded.
The ventromedial hypothalamus, ventrolateral subdivision contains oestrogen receptor type 1-positive neurons that control mating receptivity in female mice.
Unsupervised dynamical system analysis of calcium imaging data from these neurons during mating revealed a line attractor in neural state space that generates slow, ramping activity.
Neural perturbations in behaving females demonstrated relaxation of population activity back into the attractor. Population activity during mating integrated male cues to increase along this attractor, reaching a peak just before ejaculation.
Activity in the attractor dimension was positively correlated with the degree of receptivity. According to longitudinal imaging, hormone-dependent attractor dynamics manifest and vanish throughout the oestrus cycle.
These observations suggest that a hypothalamic line attractor encodes a persistent, escalating state of female sexual arousal or drive during mating.
Additionally, they demonstrate that attractors can be reversed by hormonal status over a period of days.
Abstract
A line attractor encoding a persistent internal state requires neuropeptide signaling
Internal states control survival behaviors, but their neural implementation is not well understood. Recently, we identified a line attractor in the ventromedial hypothalamus (VMH) that represents a state of aggressiveness.
Recurrent connectivity and neuromodulatory signaling can be used to implement line attractors, but there is little evidence for either.
Here, we demonstrate that neuropeptidergic signaling is necessary for line attractor dynamics in this system by using cell-type-specific CRISPR-Cas9-based gene editing combined with single-cell calcium imaging.
Adult VMH Esr1+ , neurons that co-disrupt oxytocin and vasopressin receptors reduced aggression, decreased persistent neural activity, and eliminated line attractor dynamics while only marginally reducing overall neural activity and sex- or behavior-specific tuning.
These data identify a requisite role for neuropeptidergic signaling in implementing a behaviorally relevant line attractor in mammals.
Our approach should make it easier to conduct mechanistic studies of neuroscience that combine various biological function and abstraction.
