Brain plasticity article

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New period of brain “plasticity†created with transplanted embryonic cells

March 25, 2010

Source: University of California - San Franciso

UCSF scientists report that they were able to prompt a new period of

“plasticity,†or capacity for change, in the neural circuitry of the visual

cortex of juvenile mice. The approach, they say, might some day be used to

create new periods of plasticity in the human brain that would allow for the

repair of neural circuits following injury or disease. 

The strategy – which involved transplanting a specific type of immature neuron

from embryonic mice into the visual cortex of young mice – could be used to

treat neural circuits disrupted in abnormal fetal or postnatal development,

stroke, traumatic brain injury, psychiatric illness and aging.

Like all regions of the brain, the visual cortex undergoes a highly plastic

period during early life. Cells respond strongly to visual signals, which they

relay in a rapid, directed way from one appropriate cell to the next in a

process known as synaptic transmission. The chemical connections created in this

process produce neural circuitry that is crucial for the function of the visual

system. In mice, this critical period of plasticity occurs around the end of the

fourth week of life.

The catalyst for the so-called critical period plasticity in the visual cortex

is the development of synaptic signaling by neurons that release the inhibitory

neurotransmitter GABA. These neurons receive excitatory signals from other

neurons, thus helping to maintain the balance of excitation and inhibition in

the visual system.

In their study, published in the journal Science, (Vol. 327. no. 5969, 2010),

the scientists wanted to see if the embryonic neurons, once they had matured

into GABA-producing inhibitory neurons, could induce plasticity in mice after

the normal critical period had closed.

The team first dissected the immature neurons from their origin in the embryonic

medial ganglionic eminence (MGE) of the embryonic mice. Then they transplanted

the MGE cells into the animals’ visual cortex at two different juvenile

stages. The cells, targeted to the visual cortex, dispersed through the region,

matured into GABAergic inhibitory neurons, and made widespread synaptic

connections with excitatory neurons.

The scientists then carried out a process known as monocular visual deprivation,

in which they blocked the visual signals to one eye in each of the animals for

four days. When this process is carried out during the critical period, cells in

the visual cortex quickly become less responsive to the eye deprived of sensory

input, and become more responsive to the non-deprived eye, creating alterations

in the neural circuitry. This phenomenon, known as ocular dominance plasticity,

greatly diminishes as the brain matures past this critical postnatal

developmental period.

The team wanted to see if the transplanted cells would affect the visual

system’s response to the visual deprivation after the critical period. They

studied the cells’ effects after allowing them to mature for varying lengths

of time. When the cells were as young as 17 days old or as old as 43 days old,

they had little impact on the neural circuitry of the region. However, when they

were 33-39 days old, their impact was significant. During that time, monocular

visual deprivation shifted the neural responses away from the deprived eye and

toward the non-deprived eye, revealing the state of ocular dominance plasticity.

Naturally occurring, or endogenous, inhibitory neurons are also around 33-39

days old when the normal critical period for plasticity occurs. Thus, the

transplanted cells’ impact occurred once they had reached the cellular age of

inhibitory neurons during the normal critical period. 

The finding, the team says, suggests that the normal critical period of

plasticity in the visual cortex is regulated by a developmental program

intrinsic to inhibitory neurons, and that embryonic inhibitory neuron precursors

can retain and execute this program when transplanted into the postnatal cortex,

thereby creating a new period of plasticity.

“The findings suggest it ultimately might be possible to use inhibitory neuron

transplantation, or some factor that is produced by inhibitory neurons, to

create a new period of plasticity of limited duration for repairing damaged

brains,†says author Sunil P. Gandhi, PhD, a postdoctoral fellow in the lab of

Stryker, PhD, professor of physiology and a member of the Keck Center

for Integrative Neurosciences at UCSF. “It will be important to determine

whether transplantation is equally effective in older animals.â€

Likewise, “the results raise a fundamental question: how do these cells, as

they pass through a specific stage in their development, create these windows of

plasticity?†says author G. Southwell, PhD, a student in the lab of

Arturo Alvarez-Buylla, PhD, and Muss Professor of Neurological

Surgery and a member of the Eli and Edythe Broad Center of Regeneration Medicine

and Stem Cell Research at UCSF.

The findings could be relevant to understanding why learning certain behaviors,

such as language, occurs with ease in young children but not in adults, says

Alvarez-Buylla. “Grafted MGE cells may some day provide a way to induce

cortical plasticity and learning later in life.â€

The findings also complement two other recent UCSF studies using MGE cells to

modify neural circuits. In a collaborative study among the laboratories of

Baraban, PhD, professor of neurological surgery; stein, MD, PhD,

professor of psychiatry, and Alvarez-Buylla, the cells were grafted into the

neocortex of juvenile rodents, where they reduced the intensity and frequency of

epileptic seizures. (Proceedings of the National Academy of Science, vol. 106, 

no. 36, 2009). Other teams are exploring this tactic, as well.

In the other study (Cell Stem Cell, vol. 6, issue 3, 2010), UCSF scientists

reported the first use of MGEs to treat motor symptoms in mice with a condition

designed to mimick Parkinson’s disease. The finding was reported by the lab of

Arnold Kriegstein, MD, PhD, UCSF professor of neurology and director of the Eli

and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF,

in collaboration with Alvarez-Buylla and Krys Bankiewicz, MD, PhD, UCSF

professor of neurological surgery.  

 

 

 

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