New brain connections form in clusters during learning

Researchers track structural changes during formation of new memories

SANTA CRUZ, CA--New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories ceus for social workers

The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new "dendritic spines," structures that form the connections (synapses) between nerve cells.

"For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory," said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.

In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo's lab, analyzed the spatial distribution of the newly formed synapses.

Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.

In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. "We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry," Zuo said. "The clustering of synapses may serve to magnify the strength of the connections."

Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.

The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.

"Repetitive activation of the same cortical circuit is really important in learning a new task," Zuo said. "But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories."

The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.


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In addition to Zuo and first author Min Fu, the coauthors of the paper include UCSC graduate student Xinzhu Yu and Stanford University biologist Ju Lu. This research was supported by grants from the Dana Foundation and the National Institute of Mental Health.

Autism Risk in Younger Siblings May be Higher Than Previously Thought

Autism Risk in Younger Siblings May be Higher Than Previously Thought

Parents of a child with autism spectrum disorder (ASD) face about a 19 percent chance that subsequent children will also develop ASD, according to a study partially funded by NIMH. This estimate is much higher than previous reports but may also be more accurate due to the study's size and design, according to the researchers. Their study was published August 15, 2011, online ahead of print in the journal Pediatrics ceus for social workers

Background

A few previous studies have explored the recurrence rate of ASD, or the likelihood of later-born siblings of children with ASD to also develop ASD. However, few studies addressed factors likely to influence risk estimates, such as:
Stoppage—the tendency for families to choose not to have more children after one child is diagnosed with ASD. Such families would not be included in research on ASD recurrence.
Overreporting—an error that can occur when researchers rely solely on parent reports or health records, which have been shown to inflate estimates.
Ascertainment bias—an example is overselection, which can occur when parents with one child who has ASD pay very close attention to a later child's development. They may be more likely to take part in ASD recurrence studies than other parents.

Taking a different approach, Sally Ozonoff, Ph.D., of the University of California-Davis, and colleagues evaluated data on 664 infants who were tested at 12 sites across the United States and Canada. All sites were members of the Baby Siblings Research Consortium (BSRC), an international network supported by the U.S. advocacy group Autism Speaks. All BSRC members contribute data to a centralized database that allows infant-sibling researchers to pool data across many sites and answer questions that require very large and geographically diverse samples to address.

The average age of the infant participants at the start of the study was 8 months, an age when signs of ASD are not usually present; two-thirds of the total study population were enrolled before age 6 months. All had at least one older sibling diagnosed with ASD, which was confirmed by a consortium doctor. The participants were themselves assessed for ASD multiple times in their first three years of life.

Results of the Study

Out of the total study sample, 18.7 percent of participants were diagnosed with ASD by age 3. Boys were nearly three times as likely as girls to be diagnosed with ASD. Participants who had more than one older sibling with ASD were about twice as likely to also be diagnosed with ASD, compared to participants who had only one older sibling with ASD.

Unlike some previous studies, the gender or IQ of the older sibling with ASD did not affect the later sibling's risk in the present study.

Significance

The findings indicate that ASD recurrence is 18 percent or higher, compared to 3-14 percent estimated in earlier studies. The researchers note that their study's size and design minimized the effects of stoppage, overreporting, and ascertainment bias.

Despite the strengths of their study, the researchers emphasize that recurrence estimates cannot provide information on an individual's risk. They highlight the need for careful and extensive counseling and thorough genetic work-ups for concerned parents, as well as close monitoring, especially of high-risk children, and prompt referrals for intervention by primary care providers.

What’s Next

According to the researchers, larger, population-based studies that include families of children with ASD who are not listed in the Baby Siblings Research Consortium may help to further refine recurrence estimates. Future studies will examine DNA collected from participants to examine genetic factors that may be associated with recurrence.

Reference

Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, Bryson S, Carver LJ, Constantino JN, Dobkins K, Hutman T, Iverson JM, Landa R, Rogers SJ, Sigman M, Stone WL. Recurrence Risk for Autism Spectrum Disorders: A Baby Siblings Research Consortium Study. Pediatrics. 2011 Aug 15. [Epub ahead of print] PubMed PMID: 21844053.

Support Program Can Help Caregivers Cope with Relative’s Mental Illness

A free, nationally available program can significantly improve a family's ability to cope with an ill relative's mental disorder, according to an NIMH-funded study published June 2011 in Psychiatric Services, a journal of the American Psychiatric Association.

Background
The Family-to-Family (FTF) education and support program is a free, 12-week course offered by the National Alliance on Mental Illness (NAMI). FTF is offered throughout the United States, in two Canadian provinces and in three regions in Mexico. With more than 3,500 volunteer teachers, it is supported by local donations or municipal funds. Since 1991, 250,000 family members have participated in the program. It is the most widely available education and support program for family members of individuals with mental illnesses.

Two previous studies suggested that FTF reduces caregivers' stress and helps them gain a sense of empowerment over their situation. For this most recent evaluation of the program, Lisa Dixon, M.D., M.P.H., of the University of Maryland, and colleagues aimed to determine its effectiveness using a randomized controlled trial. Half of the 318 participants were assigned to the program immediately after enrolling in the study, while the other half were waitlisted for the program for at least three months (control condition). Those who were waitlisted were free to seek assistance from other sources.

Participants were interviewed at the beginning of the three-month program and again three months later. They were asked about their problem-solving and coping skills, their overall distress level and worries about their ill relative's situation. They were also asked about their sense of empowerment to manage challenges within the family, the mental health system, and the community. They were also tested regarding their factual knowledge about mental illness.

Results of the Study
Compared to the waitlisted control group, FTF participants showed significantly greater improvements in coping with their ill relative's condition by learning more about the illness and gaining a sense of empowerment in the family, service system and community. FTF participants also showed increased acceptance of their family member's illness as well as improved problem-solving skills, compared to those who were waitlisted. Results also suggested that FTF participants' overall sense of emotional distress eased.

Significance
The researchers concluded that FTF effectively enhances coping skills among families of people with mental illness. These results echo those found in the previous qualitative studies. The researchers suggest the program can positively influence how family members solve problems and "navigate emotional difficulties" surrounding their loved one's illness.

What's Next
Additional research is needed to conclusively determine if the positive effects of FTF can improve the outcomes of the individuals with mental illness for whom the family members were taking the class.

Citation
Dixon LB, Lucksted A, Medoff DR, Burland J, Stewart B, Lehman AF, Fang LJ, Sturm V, Brown C, Murray-Swank A. Outcomes of a randomized study of a peer-taught family-to-family education program for mental illness. Psychiatric Services. 2011 June. 62(6):591-597.

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Earthquakes and Mental Health

Impact on Children and Families

Because earthquakes are unexpected and can be very destructive, being in one can be terrifying. People fear they will be injured or killed. They may be separated from family, with hours passing before knowing if their loved ones are safe. They may see collapsed buildings or other destruction and experience the horror of seeing severely injured people or even dead bodies. As they assess the damage, people may find that a relative or close friend has been killed or that their home has been destroyed. Earthquakes are particularly difficult physically and emotionally for people who are disabled or have special needs ceus for social workers

In the aftermath, people may continue to encounter sights, sounds, smells, sensations, and inner feelings that remind them-even years after-of the earthquake. These traumatic reminders can bring on distressing mental images, thoughts, and emotional/physical reactions. Common reminders include aftershocks, cracks in the wall, rumbling noises, destroyed buildings, smells of fire and smoke, the place where they experienced the earthquake, seeing people with disabilities, funerals, anniversaries of the date, and television or radio news about earthquakes.

An earthquake may serve as a reminder of prior trauma and loss, making the current reactions even worse. Post-earthquake problems with living conditions, food, water, electricity, transportation, school, work, and daily routines may make living very difficult for weeks or even months. Efforts to contend with these adversities may significantly reduce a person's coping and emotional resources, and in turn interfere with their ability to recover

Post-earthquake studies of children and adults from around the world have found that:
•Those with the most severe earthquake-related experiences and losses have the most severe and persistent posttraumatic stress and grief reactions.
•There can be widespread separation-anxiety in children and adolescents following the event.
•Depression, associated with posttraumatic stress reactions and disruption to living circumstances, often occurs after major earthquakes.
•Ongoing problems may include: marital discord; substance abuse; delinquent, aggressive or withdrawn behavior; and complaints about physical health, including headaches, stomachaches, rapid heartbeat, tightness in the chest, and appetite and digestive problems.
•Children and adolescents lose trust in the safety and security of the world, and in the ability of adults to protect them.
•Specialized trauma- or grief-focused mental health services can help children and adolescents recover from the psychological consequences of an earthquake.

Recovery: After an Earthquake



Most families will recover over time, particularly with the support of family, friends, and organizations. The length of recovery will depend, in part, upon how frightening the earthquake was, whether evacuation from home was necessary, and the extent of the damage and loss. Some families will be able to return to their normal routines rather quickly, while others will have to contend with repairing damage to their home and possessions, finding medical care, and facing financial hardship. Some families will have lost a loved one or a pet. Others will need to deal with school closings or changes in school schedules.

Children's functioning and recovery will be influenced by how their parents and caregivers cope during and after the earthquake. Children often turn to adults for information, comfort, and help. Children do best when parents and teachers remain (or at least appear) calm, answer children's questions honestly, and respond as best they can to requests.

Light Switches Brain Pathway On-and-Off to Dissect How Anxiety Works

Turns Cowering Mice into Instant Adventurers
Scientists, for the first time, have switched anxiety on-and-off in active animals by shining light at a brain pathway. Instinctively reclusive mice suddenly began exploring normally forbidding open spaces when a blue laser activated the pathway – and retreated into a protected area when it dimmed. By contrast, anxiety-like behaviors increased when an amber laser inhibited the same pathway. Researchers, supported in part by NIMH, used a virus, genetic engineering and fiber-optics to control the pathway in the brain's fear center with millisecond precision. CEUs for Social Workers

"Our findings reveal how balanced antagonistic brain pathways are continuously regulating anxiety," explained Karl Deisseroth, M.D., Ph.D., of Stanford University, a practicing psychiatrist as well as a neuroscientist. "We have pinpointed an anxiety-quelling pathway and demonstrated a way to control it that may hold promise for new types of anti-anxiety treatments."

NIMH grantees Deisseroth, Kay M. Tye, Ph.D., and colleagues, report on their findings March 17, 2011 in the journal Nature.

Optogenetic alchemy
Anxiety disorders are the most common type of psychiatric illness, affecting more than 1 in 4 people at some time during their lives. To understand the neural basis of these disorders, researchers are studying the workings of circuitry in the fear center, called the amygdala, in rodents.

Deisseroth's team has pioneered a method, called optogenetics, of experimentally activating brain activity with light. They incorporate a protein borrowed from light-reactive organisms to make brain tissue similarly light-responsive. Previously, they used this tool to activate particular types of neurons. The new study is the first to use it to reversibly manipulate a specific projection of a neuron (see picture below). It's also the first time the technique has been used to study anxiety as opposed to fear – a generalized state versus a transient reaction to an immediate threat.

The researchers borrowed a gene that codes for a light-sensitive protein from algae and delivered it to the amygdala pathway via a virus. In the algae, the protein's function is to activate a pathway that causes the organism to swim toward blue spectrum light. Hence a blue light now activated the amygdala pathway. When they wanted to inhibit the pathway in response to light, they similarly borrowed a gene from a light-responsive bacterium that codes for a protein that inhibits a pathway in response to a particular spectrum of light — in this case amber — and infected the amygdala pathway with that gene.

When the researchers optogenetically activated whole neuronal cell bodies in the amygdala, it increased anxiety-like behavior: mice hunkered down in a protected corner of a maze and wouldn't venture into more exposed areas. These and related findings led the researchers to hypothesize that they would get the same effect if they narrowed the focus of the activation to just a specific neuronal projection (see picture below).

A post-doc's eureka! moment
But it turned out that the opposite was true.

When they activated the projection with the blue laser, the engineered mice suddenly seemed to summon the courage to explore the more exposed parts of the maze that they would normally avoid (see video below).

"I was quite surprised. We did not see aversion. We did not see fear. We did not see any of these things I expected to see," said Tye, whose post-doctoral study is supported by a NIMH-funded training grant. "I suddenly got this huge, dramatic effect of reduction in anxiety-related behaviors and I had to follow it up. So I pretty much dropped my original ideas of what I was going to study during my fellowship and started pursuing this."

When the researchers blocked activity in the projection with the amber laser, the animals showed even more anxiety-like behavior than they usually do. The experiments hint at how the brain is able to regulate anxiety levels — on a millisecond timescale — by dialing activity up and down in such antagonistic amygdala pathways.

Futuristic anxiety treatment?
Tye said she and Deisseroth plan to follow up with further dissection of anxiety pathways. She also hopes to examine whether such optogenetic manipulations, sustained over hours or days, might induce long-lasting adaptations — perhaps for weeks –– in the set-points of anxiety pathways.

A future anxiety disorder treatment that might similarly target such specific pathways could, theoretically, quell anxiety instantly without producing unwanted side effects, such as drowsiness, often experienced with current anti-anxiety medications. For patients with severely debilitating anxiety, a treatment something like deep brain stimulation for depression, but more precisely targeted at a specific pathway, might someday be feasible, she suggested."Everything else in your brain should be unperturbed, because the manipulation would be so specific," explained Tye.

Video shows a mouse under "optogenetic" control while in an anxiety-producing situation. Being in elevated, open spaces makes mice anxious. So, in this "elevated-plus maze," the mouse normally stays in the arms with high walls; it normally won't venture into arms with low walls. However, this mouse has been genetically engineered to have an anxiety-quelling pathway in its fear hub activate when a blue laser shines on it via the fiber-optic cable. At those times (when the blue text appears), the animal gains courage and ventures into the normally scary places. Video speeds up a 15 minute session 10-fold.

Researchers were surprised to discover that activating the whole cell body of an amygdala neuron increased anxiety in mice, while activating just one of its projections had the opposite effect. So unraveling the secrets of how anxiety works might require dissecting the action of each such pathway individually, say the researchers.

Reference
Amygdala circuitry mediating reversible and bidirectional control of anxiety. Tye KM, Prakash R, Kim SY, Fenno LE, Grosenick L, Zarabi H, Thompson KR, Gradinaru V, Ramakrishnan C, Deisseroth K. Nature. 2011 Mar 17;471(7338):358-62. Epub 2011 Mar 9. PMID: 21389985

Stress Free Holidays

This is time of year the family calendar tends to fill up quickly. On top of regular activities and commitments, any free time on evenings and weekends may be overloaded with parties, dinners, other social events, shopping, and possibly a school or religious program or two. You may find yourself thinking, “Just a month or two and this will pass.”

Parents often dream of giving their child(ren) the best or most memorable holiday. Sometimes we need to stop and ask ourselves, “What is the best? and What is the price?” Remember that the stress, excitement, and go, go, go feeling of the holiday season not only takes its toll on you, but also your family. Children will notice when you're stressed or tired. If you're not feeling best, your child may pick up this. If you're feeling irritable, chances are your child may get a case of his or her own grumpies.

Here are some tips that may be able to help your family ease through the extra stress of the season:
•Have limits. Keep in mind, when planning for the holidays, you should have limits or expectations of what will or will not happen. This includes all areas of holiday planning. If appropriate, set a budget for gifts. Let children know in advance what they can expect so there won't be any unrealistic requests.
•Don't spread yourself too thin. It's ok for you or your child not to be actively involved in everything the season offers. If there are certain things you enjoy, individually or as a family, make a list and plans to do these things. If you find your list getting too big or out of control, maybe alternate activities yearly. In addition, saying no to one or two activities a season does not make you a humbug.
•Keep the end in sight. You may feel like the stress is going to bring your holiday happiness to an end or that it will drag on forever. Keep in mind that all too soon, the season will be behind you and life will return to “normal”. Keep an eye on what's important now.

Similarly, keep an eye on your child. If you feel that you child is becoming overwhelmed by activity or just needs a little break go for it. The tears as a result of holiday breakdown, may just add more stress to an already hectic situation.
•Find a shoulder to lean on. Keeping in contact with family and friends may give you the extra support you need to make it though the season. You don't have to do it all on your own. Don't be afraid to delegate tasks or accept offers of assistance from those close to you. If grandma is willing to give you a hand with the little ones while you run to the grocery store, take her up on her offer. Alternate shopping days with a neighbor, so each may have time alone to run errands. Holiday baking can also offer a dose of much needed stress relief as you get together with “the girls (or guys)” and share recipes and laughter.
•Remember you. Most importantly this holiday season, don't forget about keeping track of you and your family. If you're feeling run down or irritable, find something to take your mind off of your stress. Take time for a relaxing bath, a cup of cocoa, or an hour on the treadmill. What ever you want, treat yourself to your own brand of stress relief.
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The same applies to your family. If your children are getting fussy at the holiday planning tasks, find something to lift their spirits. Stop what you're doing and make a quick holiday treat that involves everyone. Get down on the floor and play a game or color. Find an outdoor activity that the whole family enjoys and take the time to enjoy it. Do something fun and not related to your holiday tasks. •Don't worry about the “To Do” list. It will be there when you get back. If by chance an item gets overlooked, it probably wasn't worth the stress it was causing you anyway. Keep these things in mind through this holiday season and enjoy!