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Inside scientists’ quest to map, modulate social circuits in autism

Micrograph of neurons in mouse brain.

Short circuit: Stimulation of neurons that extend from the prefrontal cortex to the amygdala (pink) causes social problems in mice.

One of the biggest mysteries in autism research is understanding how the condition’s discrete set of traits emerges from a multitude of genetic and environmental factors. Over the past decade, scientists have homed in on a possible explanation: Autism’s diverse influences may all affect the same neural circuits, or networks of neurons that work in concert.

Researchers are gradually building a ‘road map’ of the neural circuits relevant to autism, charting key pathways that connect autism-linked brain regions, including the amygdala, prefrontal cortex and cerebellum. In particular, a growing number of studies have revealed circuits that underpin social problems in mouse models of the condition.

“Really the goal is: Can we think about understanding the circuit to actually benefit people with [autism]?” says Peter Tsai, assistant professor of neurology at the University of Texas Southwestern in Dallas.

Treatments that alter activity in other neural circuits, such as those governing movement, already exist for Parkinson’s disease and other neurological conditions1. Mapping the social circuits altered in autism mouse models may provide a similar avenue for therapy in autistic people, says Erik Carlson, assistant professor of psychiatry at the University of Washington in Seattle.

“As we get a picture of what the circuits are, and potentially how to target them and modulate them, I definitely think [manipulating circuits] is an avenue that is promising,” he says.

One possibility, Tsai says, is building on the knowledge researchers have gained using techniques such as optogenetics and chemogenetics, which use light and chemicals, respectively, to toggle neural circuit activity in mice.

Cerebellar circuits:

Tsai and his colleagues have focused on a neural circuit connecting the cerebellum to the medial prefrontal cortex2. Both regions are implicated in autism traits, such as having difficulty making predictions in social situations and problems with higher-order cognitive functions such as planning.

Tsai’s team studied mice with mutations in a gene called TSC1, which in people can lead to a condition called tuberous sclerosis, characterized by epileptic seizures, benign tumors and, in about 40 to 50 percent of cases, autism.

Previously they mutated the gene in cerebellar neurons known as Purkinje cells, dampening the cells’ activity and causing autism-like social problems and repetitive behaviors in the mice3. Stimulating Purkinje cells in a part of the cerebellum known as right crus 1, which connects to the medial prefrontal cortex, resolved the mice’s social difficulties — but not their repetitive behaviors.

In July in Nature Neuroscience, the team published new results showing that inhibiting the posterior vermis — a different part of the cerebellum that also sends signals to the prefrontal cortex — reverses the mice’s repetitive behaviors instead.

Inhibiting either part of the cerebellum spurs excess activity in the medial prefrontal cortex, the researchers note. And tamping down this excess also curbs the mice’s social difficulties and repetitive behaviors. Inhibiting the ventromedial thalamus, a hub-like region where signals from the cerebellum converge before arriving at the prefrontal cortex, resolves all of the animals’ autism-like behaviors.

The results jibe with a prevailing theory that autism arises from a signaling imbalance between neurons, Tsai says. By probing neural circuits and observing what regions of the brain are overly activated or dampened, researchers can learn more about the origins of this imbalance.

The study reveals only half the picture, however, because a different set of neurons extends in the opposite direction — from the cortex back to the cerebellum. These connections form the other half of a loop that governs social behavior. Tsai says his team also intends to manipulate activity in this half of the circuit in future studies.

And the circuit interacts with other brain regions, too. The cerebellum also connects to the ventral tegmental area, a region of the brain involved in encoding and processing rewards. Inhibiting this circuit also makes mice less sociable, according to a study last year4.

“The ventral tegmental area is kind of a hub of many within the broader distributed sociability circuit network,” says Matthew Anderson, associate professor of pathology at Harvard Medical School, who was not involved in last year’s study. His own work has shown that dampening excessive neuronal activity in the ventral tegmental area can alter sociability in a mouse model of autism5.

Together the findings show that the cerebellum — classically thought of as a regulator of motor function — plays a critical role in social behaviors through its connections with other brain regions implicated in autism, says Aleksandra Badura, assistant professor of neuroscience at Erasmus University in Rotterdam, the Netherlands, who was not involved in the studies.

“I think that this is now a nail to the coffin for everyone who claimed that the cerebellum has just this motor function,” Badura says.

Zooming in:

Another circuit extends from the prefrontal cortex to a brain region called the basolateral amygdala, and it, too, is linked to autism-like social behaviors in mice6. Altered activity in the amygdala is associated with core autism traits, including difficulties in processing social information.

Using a method called retrograde labeling, researchers traced signals from two parts of the prefrontal cortex — the infralimbic and prelimbic cortices — to the amygdala. The infralimbic pathway was particularly active when mice were socially interacting, whereas prelimbic neurons were active to a lesser extent.

Silencing the infralimbic cortex or stimulating the prelimbic cortex caused mice to avoid social interactions with other mice, the researchers found, suggesting these two subcircuits play antagonistic roles in regulating social behavior. They published their results in July in Cell Reports.

In another part of the experiment, the researchers gave mice a mild electric foot shock and saw that it activated the prelimbic circuit. When they later reactivated this circuit without giving a foot shock, the mice again avoided other mice. These findings suggest that the two subcircuits code for opposing emotional responses.

“Intriguingly, we found that different subregions of the prefrontal cortex have differential effects on social approach behavior,” says lead investigator Damon Page, associate professor of neuroscience at the Scripps Research Institute in Jupiter, Florida.

The two subcircuits may connect to different kinds of cells in the amygdala that respond to positive and negative stimuli, Page speculates.

Circuit quest:

As teams continue their search for neural circuits relevant to autism’s social traits, they need to address several pressing questions. Perhaps the most important of these is understanding how these neural circuits relate to one another — and to the entire brain, Tsai says.

“There are tons and tons of regions of the brain that have been implicated [in autism],” he says. “I think it’s important to try to understand what that wide network is and then taking a step back from that and asking: What is it actually doing?”

For his own research on the cerebellum, that means not only identifying neural circuits that are critical for regulating autism-like behaviors, but also understanding how this regulation takes place at a molecular level, he says.

Another looming question is what kinds of interventions could target these neural circuits in humans, Carlson says. The amygdala, thalamus and prefrontal cortex all contribute to autism traits, but they sit too deep inside the brain for existing noninvasive brain stimulation techniques, which typically deliver electricity or magnetic pulses, to manipulate brain activity.

Deep brain stimulation, a technique that involves implanting small electrodes inside the brain, can reach these areas, but researchers don’t understand social circuits well enough yet to be able to use it on them, Carlson says.

Manipulating the cerebellum, which is not so deep, may offer a more feasible way to tap into broader social circuits affected in autism, Tsai says. But further studies are needed to map out in detail the intricate circuitry connecting the cerebellum to other brain regions.

“It’s like a road map,” he says. “You can fix one road, but if there are thousands of other streets that are impacted and changed, it’s not going to work. Ultimately, you need to know the bigger picture.”

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THIS NOTICE DESCRIBES HOW MEDICAL INFORMATION ABOUT YOU MAY BE USED AND DISCLOSED AND HOW YOU CAN GET ACCESS TO THIS INFORMATION. PLEASE REVIEW IT CAREFULLY.

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This Notice of Privacy Practices describes how we may use and disclose your protected health information to carry out treatment, payment or health care operations and for other purposes that are permitted or required by law. It also describes your rights to access and control your protected health information. Protected health information is information about you, including demographic information, that may identify you and that relates to your past, present or future physical or mental health or condition and related health care services.

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We are required to abide by the terms of this Notice of Privacy Practices. We may change the terms of our Notice of Privacy Practices at any time. The new Notice of Privacy Practices will be effective for all protected health information that we maintain at that time. Upon your request, we will provide you with any revised Notice of Privacy Practices. You may request a revised version by calling or writing our Privacy Officer and requesting that a revised copy be sent to you in the mail or asking for one at the time of your next appointment.

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Your protected health information may be used and disclosed by our office staff others outside of our office who are involved in your care and treatment for the purpose of providing health care services to you.
Your protected health information may also be used and disclosed to pay your health care bills and to support the operation of our practice.
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1. Treatment: We will use and disclose your protected health information to provide, coordinate, or manage your health care and any related services. This includes the coordination or management of your health care with another provider.
For example, we would disclose your protected health information, as necessary, to a home health agency that provides care to you. We will also disclose protected health information to other healthcare providers who may be treating you.
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(vi) Legal Proceedings: We may disclose protected health information in the course of any judicial or administrative proceeding, in response to an order of a court or administrative tribunal (to the extent such disclosure is expressly authorized), or in certain conditions in response to a subpoena, discovery request or other lawful process.

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(viii) Research: We may disclose your protected health information to researchers when their research has been approved by an institutional review board that has reviewed the research proposal and established protocols to ensure the privacy of your protected health information.

(ix) Criminal Activity: Consistent with applicable federal and state laws, we may disclose your protected health information, if we believe that the use or disclosure is necessary to prevent or lessen a serious and imminent threat to the health or safety of a person or the public. We may also disclose protected health information if it is necessary for law enforcement authorities to identify or apprehend an individual.

(x) Military Activity and National Security: When the appropriate conditions apply, we may use or disclose protected health information of individuals who are Armed Forces personnel (1) for activities deemed necessary by appropriate military command authorities; (2) for the purpose of a determination by the Department of Veterans Affairs of your eligibility for benefits, or (3) to foreign military authority if you are a member of that foreign military services. We may also disclose your protected health information to authorized federal officials for conducting national security and intelligence activities, including for the provision of protective services to the President or others legally authorized.

(xi) Workers' Compensation: We may disclose your protected health information as authorized to comply with workers' compensation laws and other similar legally established programs.
5. Other Permitted and Required Uses of Disclosures That Require Providing You the Opportunity to Agree or Object
We may use and disclose your protected health information in the following instances. You have the opportunity to agree or object to the use or disclosure of all or part of your protected health information. If you are not present or able to agree or object to the use or disclosure of the protected health information, then we may, using professional judgment, determine whether the disclosure is in your best interest.

Others Involved in Your Health Care or Payment for our Care:

Unless you object, we may disclose to a member of your family, a relative, a close friend or any other person you identify, your protected health information that directly relates to that person's involvement in your health care. If you are unable to agree or object to such a disclosure, we may disclose such information as necessary if we determine that it is in your best interest based on our professional judgment. We may use or disclose protected health information to notify or assist in notifying a family member, personal representative or any other person that is responsible for your care of your location, general condition or death. Finally, we may use or disclose your protected health information to an authorized public or private entity to assist in disaster relief efforts and to coordinate uses and disclosures to family or other individuals involved in your health care.
6. Uses and Disclosures of Protected Health Information Based upon Your Written Authorization Other uses and disclosures of your protected health information will be made only with your written authorization, unless otherwise permitted or required by law as described below. You may revoke this authorization in writing at any time. If you revoke your authorization, we will no longer use or disclose your protected health information for the reasons covered by your written authorization. Please understand that we are unable to take back any disclosures already made with your authorization.
C. YOUR RIGHTS
Following is a statement of your rights with respect to your protected health information and a brief description of how you may exercise these rights
1. You have the right to inspect and copy your protected health information
This means you may inspect and obtain a copy of protected health information about you for so long as we maintain the protected health information. You may obtain your medical record that contains medical and billing records and any other records that we use for making decisions about you. As permitted by federal or state law, we may charge you a reasonable copy fee for a copy of your records.
2. You have the right to request a restriction of your protected health information
This means you may ask us not to use or disclose any part of your protected health information for the purposes of treatment, payment or health care operations. You may also request that any part of your protected health information not be disclosed to family members or friends who may be involved in your care or for notification purposes as described in this Notice of Privacy Practices. Your request must state the specific restriction requested and to whom you want the restriction to apply.

We are not required to agree to a restriction that you may request. If we agree to the requested restriction, we may not use or disclose your protected health information in violation of that restriction unless it is needed to provide emergency treatment. With this in mind, please discuss any restriction you wish to request with your health provider.

You may request a restriction by making your request in writing to our Privacy Officer. In your request, you must tell us (1) what information you want to limit; (2) whether you want to limit our use, disclosure, or both; and (3) to whom you want the limits to apply, for example, disclosures to your spouse.
3. You have the right to request to receive confidential communications from us by alternative means or at an alternative location
We will accommodate reasonable requests. We may also condition this accommodation by asking you for information as to how payment will be handled or specification of an alternative address or other method of contact. We will not request an explanation from you as to the basis for the request. Please make this request in writing to our Privacy Officer.
4. Your may have right to amend your protected health information
This means you may request an amendment of protected health information about you in a designated record set for so long as we maintain this information. In certain cases, we may deny your request for an amendment. If we deny your request for amendment, you have the right to file a statement of disagreement with us and we may prepare a rebuttal to your statement and will provide you with a copy of any such rebuttal. Please contact our Privacy Officer if you have questions about amending your medical record.
5. You have the right to receive an accounting of certain disclosures we have made, if any, of your protected health information This right applies to disclosures for purposes other than treatment, payment or health care operations as described in this Notice of Privacy Practices. It excludes disclosures we may have made to you if you authorized us to make the disclosure, to family members or friends involved in your care, or for notification purposes, for national security or intelligence, to law enforcement (as provided in the privacy rule) or correctional facilities, as part of a limited data set disclosure. The right to receive this information is subject to certain exceptions, restrictions and limitations.
6. You have the right to obtain a paper copy of this notice from us
upon request, even if you have agreed to accept this notice electronically.
D. COMPLAINTS
You may complain to us or to the Secretary of Health and Human Services if you believe your privacy rights have been violated by us. You may file a complaint with us by notifying our Privacy Officer of your complaint. We will not retaliate against you for filing a complaint

You may contact our Privacy Officer at (704) 824-7800 for further information about the complaint process.

This notice was published and becomes effective on August l, 2011.