Researchers study brain circuitry shift, PTSD

   (NIH) - 1/24/2015 - People with anxiety disorders, such as post traumatic stress disorder (PTSD), often experience prolonged and exaggerated fearfulness. Now, an animal study suggests that this might involve disruption of a gradual shifting of brain circuitry for retrieving fear memories. Researchers funded by the National Institutes of Health have discovered in rats that an old fear memory is recalled by a separate brain pathway from the one originally used to recall it when it was fresh.
  After rats were conditioned to fear a tone associated with a mild shock, their overt behavior remained unchanged over time, but the pathway engaged in remembering the traumatic event took a detour, perhaps increasing its staying power.
   “While our memories feel constant across time, the neural pathways supporting them actually change with time,” explained Gregory Quirk, Ph.D of the University of Puerto Rico School of Medicine, in San Juan, a grantee of NIH’s National Institute of Mental Health (NIMH). “Uncovering new pathways for old memories could change scientists’ view of post-traumatic stress disorder, in which fearful events occur months or years prior to the onset of symptoms.”
   A research team led by Quirk and Fabricio Do-Monte, D.V.M., Ph.D., report on their findings in the January 19, 2015, issue of Nature.
   Immediately after fear conditioning, a circuit running from the prefrontal cortex, the executive hub, to part of the amygdala, the fear hub, was engaged to retrieve the memory. But several days later, Quirk and colleagues discovered that retrieval had migrated to a different circuit – from the prefrontal cortex to an area in the thalamus, called the paraventricular region (PVT). The PVT, in turn, communicates with a different central part of the amygdala that orchestrates fear learning and expression.
   The Quirk team spotted the moving memory using a genetic/laser technique called optogenetics, which can activate or silence specific pathways to tease apart their workings.
   The researchers say that the PVT may serve to integrate fear with other adaptive responses, such as stress, thereby strengthening the fear memory.
   “In people with anxiety disorders, any disruption of timing-dependent regulation in retrieval circuits might worsen fear responses occurring long after a traumatic event,” Quirk suggested.
   In the same issue of Nature, NIMH grantees Bo Li, Ph.D. and Mario Penzo, Ph.D. of Cold Spring Harbor Laboratory in New York, and colleagues, reveal how the long-term fear memory circuit works in mice to translate detection of stress into adaptive behaviors.
   Li and colleagues independently discovered the same shift in memory retrieval circuitry occurring, over time, after fear conditioning in mice. Using powerful genetic-chemical, as well as optogenetic, methods to experimentally switch pathways on and off, they showed conclusively that neurons originating in the PVT regulate fear processing by acting on a class of neurons that store fear memories in the central amygdala area.
   The Li team traced this activity in the PVT to the action of a messenger chemical, brain-derived neurotrophic factor (BDNF), which has previously been implicated in mood and anxiety disorders. For example, altered BDNF expression has been linked to PTSD.
   BDNF from the PVT, working via a specific receptor, activated the memory-storing amygdala neurons. Simply infusing BDNF into the central amygdala area caused mice to freeze in fear, suggesting that it not only enables the formation of fear memories, but also the expression of fear responses.
   Grants: MH058883, MH086400, GM061838, MH101214
   For more information, visit http://www.nimh.nih.gov.

References

-- Do-Monte HF, Quinones-Laracuente K, Quirk, GJ. A temporal shift in the circuits mediating retrieval of fear memory. Nature, Dec. ??, 2014.
-- Penzo MA, Robert V, Tucciarone J, De Bundel D, Wang M, Van Aeist L, Varvas M, Parada LF, Palmiter R, He M, Huang ZJ, Li B. The paraventricular thalamus controls a central amygdala fear circuit. Nature Dec. ??, 2014.
  Source: National Institutes of Health

Stem Cell Transplants May Halt MS Progression

   (NIH) - 12/31/2014 - Three-year outcomes from an ongoing clinical trial suggest that high-dose immunosuppressive therapy followed by transplantation of a person's own blood-forming stem cells may induce sustained remission in some people with relapsing-remitting multiple sclerosis (RRMS). RRMS is the most common form of MS, a progressive autoimmune disease in which the immune system attacks the brain and spinal cord. The trial is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and conducted by the NIAID-funded Immune Tolerance Network (ITN).
   Three years after the treatment, called high-dose immunosuppressive therapy and autologous hematopoietic cell transplant or HDIT/HCT, nearly 80 percent of trial participants had survived without experiencing an increase in disability, a relapse of MS symptoms or new brain lesions. Investigators observed few serious early complications or unexpected side effects, although many participants experienced expected side effects of high-dose immunosuppression, including infections and gastrointestinal problems. The three-year findings are published in the Dec. 29, 2014, online issue of JAMA Neurology.
   “These promising results support the need for future studies to further evaluate the benefits and risks of HDIT/HCT and directly compare this treatment strategy to current MS therapies,”  NIAID Director Anthony S. Fauci said. “If the findings from this study are confirmed, HDIT/HCT may become a potential therapeutic option for people with this often-debilitating disease, particularly those who have not been helped by standard treatments.”
   Scientists estimate that MS affects more than 2.3 million people worldwide. Symptoms can vary widely and may include disturbances in speech, vision and movement. Most people with MS are diagnosed with RRMS, which is characterized by periods of relapse or flare up of symptoms followed by periods of recovery or remission. Over years, the disease can worsen and shift to a more progressive form.
  In the study, researchers tested the effectiveness of HDIT/HCT in 25 volunteers with RRMS who had relapsed and experienced worsened neurological disability while taking standard medications. Doctors collected blood-forming stem cells from participants and then gave them high-dose chemotherapy to destroy their immune systems. The doctors returned the stem cells to the participants to rebuild and reset their immune systems.
   “Notably, participants did not receive any MS drugs after transplant, yet most remained in remission after three years,” NIAID Division of Allergy, Immunology and Transplantation Director Daniel Rotrosen said. “In contrast, other studies have shown that the best alternative MS treatments induce much shorter remissions and require long-term use of immunosuppressive drugs that can cause serious side effects.”
  The study researchers plan to follow participants for a total of five years, recording all side effects associated with the treatment. Final results from this and similar studies promise to help inform the design of larger trials to further evaluate HDIT/HCT in people with MS.
   The work was sponsored by NIAID, NIH, and conducted by the ITN (contract number N01 AI015416) and NIAID-funded statistical and clinical coordinating centers (contract numbers HHSN272200800029C and HHSN272200900057C). The ClinicalTrials.gov identifier for the study High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is NCT00288626.
   Source: National Institutes of Health

Defense Contractor to Pay $27.5 Million

  (DOJ) - 12/20/2014 - Lockheed Martin Integrated Systems (LMIS) has agreed to pay $27.5 million to resolve allegations that it violated the False Claims Act by knowingly overbilling the government for work performed by LMIS employees who lacked required job qualifications. 

   The settlement was announced today by Acting Assistant Attorney General Joyce R. Branda for the Justice Department’s Civil Division and U.S. Attorney Paul J. Fishman for the District of New Jersey.
   “Contractors that knowingly bill the government in violation of contract terms will face serious consequences,”Acting Assistant Attorney General Branda said.  “The department will ensure that those who do business with the government, and seek taxpayer funds, do so fairly and in accordance with the applicable rules.”
   LMIS is a subsidiary of Lockheed Martin Inc., which is headquartered in Bethesda, Maryland.  The alleged labor mischarging occurred on the Rapid Response (CR2) contract and the Strategic Services Sourcing (S3) contract, both issued by the U.S. Army Communication and Electronics Command (CECOM).  CECOM is located at Fort Monmouth, New Jersey, and at the Aberdeen Proving Group in Maryland.
   The purpose of the CR2 and S3 contracts is to provide rapid access to products and services to be provided to the Army in Iraq and Afghanistan. Individual task orders then are separately negotiated, based on these contracts, to quickly meet the needs of CECOM.  LMIS allegedly violated the terms of the contracts by using under-qualified employees who were billed to the United States at the rates of more qualified employees.  The overbilling allegedly resulted in greater profit for LMIS.
   “This settlement demonstrates the commitment of the Defense Criminal Investigative Service (DCIS) and our partners to vigorously pursue alleged violations of the False Claims Act,” DCIS Northeast Field Office Special Agent Craig Rupert said.  “All contractors doing business with the federal government are expected to abide by the acquisition rules no matter who they are.  Investigations of such allegations are necessary to protect American taxpayers and our warfighters.”
  Source: Dept. of Justice