Entries in neuroscience (11)


Nanoparticle antioxidants offer potential Alzheimer’s therapy

Mitochondria have been known as a cell’s power plants. The abnormal generation of reactive oxygen species (ROS) from dysfunctioning mitochondria can cause neuronal cell death. This pathologic process is a key factor to a number of neurodegenerative diseases, including Alzheimer’s disease (AD). Amyloid-β peptides, which are believed to cause AD, can interact with resident proteins inside mitochondria, inducing abnormal production of ROS. Thus, ROS scavengers, such as antioxidant molecules, targeting mitochondria would be useful for prevention and early state treatment of AD.

A research team lead by Taeghwan Hyeon designed and synthesized triphenylphosphonium-conjugated ceria (CeO2) nanoparticles (TPP-ceria NPs), which can selectively localize in mitochondria and behave as strong ROS scavengers. These nanoparticles function in a recyclable manner by shuttling between Ce(III) and Ce(IV) oxidation states. The study of an AD mouse model indicates that the nanoparticles effectively suppress neuronal cell death by protecting them from ROS. This research has paved the road for the development of novel strategy to prevent and treat AD and other neurodegenerative diseases. 



ACS Nano 2016, 10, 2860−2870.


GABA mediated vulnerable developmental periods: a potential target for diseases such as epilepsy and autism

Proper excitation-inhibition balance is crucial for normal brain function and particularly during critical periods of development, when neurons are still immature and brain circuits not yet fully formed. 

For example increases in neuronal excitability through inactivation of Kv7 voltage gated K+ channel current results in epilepsy in mice. A recent study by Marguet et al. showed that restoring excitation-inhibition balance in these mice during a critical window (first two weeks of life) prevents later development of epilepsy. The authors used Bumetanide, an FDA approved NKCC1 antagonist (cation-chloride cotransporter) to reduce intracellular chloride concentration and thereby reduce excitatory action of GABA in immature neurons. Notably, treatment during the critical window with Bumetanide was able to normalize network activity and prevent later epileptogenesis before the onset of symptoms in these mice. 

GABA mediated hyper-excitability in immature brain circuits has also been identified in autism models. In 2014, Tyzio and colleagues showed that maternal treatment with the same drug, Bumetanide, restored electrophysiological and behavioral phenotypes in rodent models of autism (Valproate and Fragile X). 

Translation of these findings to humans is undoubtedly very difficult. A first step are ongoing studies investigating the effect of Bumetanide treatment in individuals with autism and manifest epilepsy. However, preclinical studies investigating the basic underlying mechanisms may help understand the importance of excitation and inhibition of normal network activity and suggest future research avenues to go as far as investigating the potential for disease prevention in some cases. 


Marguet et al. Nature Medicine 2015

Tyzio et al. Science 2014


Manipulating Memory: From Inception to Neuroscience 

In Christopher Nolan's 2010 movie, Inception, Leonardo DiCaprio plants an idea or a specific memory in another person’s subconscious through a dream. Is this possible? Might be. MIT neuroscientists Liu and Ramire et al. have shown that they were able to create false memories in mice via optogenetics. Optogenetics is a technique that utilizes light stimuli to control specific genetically modified cells in living tissue via light-gated ion channel.

In their study, the mice were firstly subjected to a safe environment, Box A. Memories of this new environment were recorded in certain cells, which were programmed to respond to pulses of light. By applying light pulses, the mice will recall the memory of Box A. Then the mice were placed in a completely different environment, Box B, where the mice were subjected to foot shocks, with simultaneous delivery of light pulses into their brains to reactivate the memory of Box A. This resulted in a negative association between the light-reactivated memory of Box A and the foot shocks that the mice obtained in Box B. When the researchers put the mice back into Box A, it was observed that the mice displayed heightened fear responses. A false fear memory was implanted into the mice brain via artificial means.

This work has shown that memories can be altered during the recall process. The researchers pointed out that recall could make memories more labile and external information might be incorporated into existing memories occasionally over time. As Ramirez explained in their TEDx Boston talk, “The mind, with its seemingly mysterious properties, is actually made of physical stuff that we can tinker with.” Their work illustrates the increasing ability of neuroscientists to control, manipulate, and engineer memory in the brain.



(1) Liu, X., Ramirez, S., Pang, P. T., Puryear, C. B., Govindarajan, A., Deisseroth, K., Tonegawa, S. Nature, 2012, 484 (7394), 381-385.

(2) Ramirez, S., Liu, X., Lin, P. A., Suh, J., Pignatelli, M., Redondo, R. L., Tonegawa, S. Science, 2013, 341(6144), 387-391.

(3) https://www.youtube.com/watch?v=kDXJhxLzmBQ


The next five minutes could really help: Resting state fMRI predicts antipsychotic treatment response 

In Friday’s online issue of The American Journal of Psychiatry, Dr. Deepak Sarpal and colleagues published a ground-breaking new report where antipsychotic treatment response could be predicted using resting state fMRI.

Resting state function magnetic resonance imaging, or rs-fMRI for short, is a technique where changes in blood flow can be measured in the brain and plotted on the basis that increased blood flow means increased brain activity (and less blood flow means lower brain activity).  This method can reveal single hotspots (or coldspots) of activity, but with very high time resolution, can be used to identify how different regions of the brain are connected.  Using an identified hotspot as a ‘seed,’ fMRI analysis allows a mapping of when and where other changes happen in the brain during the resting period to create a network of functional connectivity.

Beginning with a ‘discovery’ cohort, Sarpal and colleagues found that in first-episode schizophrenia patients, analysis of a 5-minute rs-fMRI scan revealed that those who would later showed a lasting response to antipsychotic drug treatment (risperidone or aripiprazole) had lower connectivity stemming from the striatum.  The striatum is a region in the middle of the brain and, as a central part of the brain’s reward system, is known to have dysregulated function in schizophrenia. The current study found the striatum to be integrating measureable signals with 91 other functional connections.

By setting a threshold level of striatal connectivity, the authors found significant predictive power of their system in testing rs-fMRI data from a matched but independent ‘generalizability’ cohort of patients who were treated for an acute psychotic episode. Again, those patients who would go on to respond from antipsychotic therapy had subthreshold levels of striatal connectivity prior to intervention. 

A major step forward from this paper is identifying patients where treatment is likely to work – and at the same time, highlighting those patients who are likely to be treatment non-responders.

A key aspect of the work in our lab is in understanding the molecular changes associated with the normal and diseased brain. Using dual-modality imaging, we design experiments that can link fMRI with PET imaging to visualize specific molecules and enable understanding of how the regional density of a receptor/protein target relates to functional changes in blood flow. The recent findings by Dr. Sarpal et al could quickly open new doors to highlight what divides patient groups; by applying novel PET tools, we are poised to advance understanding of underlying protein targets could be exploited in next-generation therapeutics.


Sarpal DK, et al “Baseline Striatal Functional Connectivity as a Predictor of Response to Antipsychotic Drug Treatment” American Journal of Psychiatry, Aug. 28, 2015.

AJP in Advance (doi: 10.1176/appi.ajp.2015.14121571).


The state of medical neuroscience: how can PET fill the gaps?

A couple of months ago I had an opportunity to attend the World Medical Innovation Forum hosted by Partners Health Care. This year’s forum focusing on Neuroscience brought together expertise from both industry and academia to discuss the current state of research for psychiatric and neurologic disease. This conference was rather unique in that it gave the audience a full spectrum view of how these diseases impact the world. While thoroughly covering the latest medical information on new pathological targets and therapeutic advances, the presenters also included patients and patients’ families, which offered a unique perspective that helped to characterize the disease as more than just a molecular mishap. While the science can often be slow and wrought with frustration, reconnection with patients and advocates for disease research can quickly reset the stage to remind you of the end goal.

The forum did not include any detailed data presentations, but offered an informal, conversational approach to discussing the current interests of both industry and academic researchers. With respect to Alzheimer’s disease, the general consensus seemed to be that the current spectrum of therapies targets the removal of dysfunctional proteins (Aβ, Tau), but this might not be enough once the tissue is damaged. Industry called to academic researchers in basic research to identify targets for early diagnosis so that the disease can be caught before there is permanent damage. They also highlighted the need for regenerative methods to help repair the damaged tissue once the diseased tissue is removed. In this same vein, regenerative medicine methods were proposed where dopamine neurons will be implanted in Parkinson’s disease patients to replace those lost to the disease. In regards to MS research, the search for curative, neuroprotective, and restorative therapy continues to stop, prevent and repair the insult of neuronal damage brought on by this disease.

From a neuroimaging perspective, many stages in this research offer a potential for advancement with PET imaging. In vivo imaging provides an opportune view into the living brain whereby early AD biomarkers could be tracked non-invasively and evaluated with disease progression. In regenerative medicine, molecular imaging provides a chance to visualize whether newly implanted neurons are expressing proper receptors and neurotransmitters are interacting accordingly. Finally, when regenerative therapies are ready, PET imaging can not only provide structural proof, but hopefully also confirm that this new structure is molecularly sound.