|As mice learned a new task, repeated imaging of the same neurons
over one-day intervals showed remodeling of synapses, with new branches
(dendritic spines) forming and others eliminated during training. Image courtesy ofXu et al|
The brain is a dynamic
mass of interconnected circuits, exquisitely engineered to maintain balance and
stability in the midst of constant change. Unraveling its structural and
functional connectivity in health and disease has been a dominant theme in
modern neuroscience, and a recent symposium
at the New York Academy of Sciences offered some insight into what we’ve
The primary focus of
the afternoon was the synapse, the point of contact between neurons, with
particular emphasis on dendritic
spines, key players in excitatory neurotransmission.
"Why do we look at
spines so much?" asked David Sulzer, professor of neurology, psychiatry,
and pharmacology at Columbia University. "They're easy to see." For
visualizing other aspects of neurotransmission, such as presynaptic activity,
"our techniques are not so good, and we're missing a lot of interesting
information if we ignore them."
That said, dendritic
spines provide a useful index of change in connectivity, as was evident in
Bruce McEwen's discussion of stress.
"We now know that
dendrites can grow or shrink with experiences good and bad," said McEwen, professor
of neuroscience at Rockefeller University and a member of the Dana Alliance for
Brain Initiatives. "With repeated stress, apical dendrites of
the CA3 region of the hippocampus shrink in a reversible manner. Neurogenesis
is reduced by certain stressors, enhanced by enriched environment and
European hamster offers "one of the most dramatic example of [such]
plasticity," he said. When its day length is artificially shortened,
"the atrophy of apical dendrites occurs within hours, and can be reversed
equally rapidly when you wake the animal up." It appears that de- and repolymerization of the
underlies these quick structural changes, he said.
corticosteroid secretion triggers excessive glutamine release, which shrinks
dendrites over time. Other mediators, growth factors, cell surface and adhesion
molecules, and neurotransmitter systems, are also involved, McEwen said.
experience causes alterations in neural architecture, and in behavior," he
said. Although effects were first studied and are particularly evident in the
hippocampus, they are distributed widely. When animals are stressed, dendrites shrink
in the prefrontal cortex (PFC), leading to their expansion in the basolateral amygdala
and orbitofrontal cortex, with associated increased anxiety and vigilance, and their
shrinkage in the medial amygdala, which may explain reduced social interaction.
The system normally returns to its pre-stress state when danger passes.
In a human study, stress
in medical students preparing for exams was associated with reduced cognitive
flexibility and functional connectivity within the PFC. The alterations
promptly reversed after a vacation.
Such resilience apparently declines with age
and in people with mood and anxiety disorders. Neurogenesis stimulated by
regular exercise or intense learning experiences can redress some of these
losses, however, as can treatment with antidepressant drugs.
effects on brain structure and cognitive function can be best described as
"an inverted U-shaped
dose-response curve," McEwen said. "Acutely, adrenal steroids and
excitatory amino acids enhance synaptic function and improve some aspects of
memory. More intense or prolonged stressors have the opposite effect."
Wenbiao Gan, professor
of neuroscience and physiology at NYU Medical Center, detailed the microanatomy
of memory. "Synaptic connections are highly plastic," he said.
"These changes are important for development, adaptation to the
environment, and learning." At the same time, stability in these circuits
is essential to retain information over time.
"To understand the basis of learning and
memory, we developed a way to directly image dendritic spines in the mouse
cortex," he said.
microscopy, Gan and colleagues observed the same neurons over hours, days and
months. "Most spines were remarkably stable," he said: In the adult
cortex, some 70 percent of those seen at 5 months remained 19 months later. At
the same time, a substantial number of new spines were formed, some long-lasting.
experiments in which young mice were trained to adjust their gait to follow accelerations
of a motorized device. The rate of spine formation doubled after a half-hour of
training for the first few days, but slackened off afterward. "It’s when you
learn something new that you form new connections," he said. Over succeeding
weeks, most newly-formed spines disappeared; 16 months later, only a small
With this process—initial
creation of many new spines, followed by selection and stabilization— "the
brain can keep and integrate new connections. A small number suffice to
modulate circuit function without disrupting the connectivity behind storage of
previous memories," Gan said.
related to learning isn't uniform, he observed, but limited to subsets of a
neuron's branches. Training in a different task spurs spine formation in a different
Another microscopy study
suggested sleep’s role in the dendritic changes underlying learning. "Without sleep, branch-specific
formation of new spines was severely reduced," Gan said. Apparently, the neurons
engaged by the motor task are reactivated during non-REM sleep.
A second training
period didn't promote spine formation as much as sleep. "It's better to
sleep after learning than to keep studying," he concluded.
Two other talks
suggested that autism involves abnormal connectivity in the brain. Bernardo
Sabatini, professor of neurobiology at Harvard University, focused on the basal
ganglia, a midbrain region that links reward to motor activity and whose dysfunctions
are apparently involved in disorders as diverse as Parkinson’s and Huntington’s
disease, obsessive compulsive disorder, and drug addiction.
“There is a case
building in the literature that the region makes a contribution to autism” as
well, Sabatini said. The core features of autism—disturbed language
development, aberrant eye contact, and repetitive movements—“all can be mapped
onto the basal ganglia.”
He described research
suggesting that synaptic connections between the cortex and basal ganglia
develop in response to input from the cortex, and that modifying cortical
activity in very young animals can influence their number and strength.
Disruptions in this
process early in development might account for the repetitive movements (e.g.
hand-flapping, rocking) common in autism, which apparently involve recurrent
signals cycling through the basal ganglia. Sabatini described research focusing
on a gene expressing a protein that regulates synapse formation, linking its
abnormalities to hypergrooming, a behavioral abnormality in mice that resembles
such stereotypical behaviors. Deletions or truncations in the part of the human
genome containing the equivalent gene are associated with rare forms of autism,
David Sulzer summarized
research linking autistic spectrum disorders to a deficit in synaptic pruning.
Normally, synapses proliferate profusely in infancy and are cut back by late
adolescence: A post-mortem study found that the length and number of dendritic
spines decreased by 50 percent in normal brains between childhood and the teen
years, but just 15 percent in autistic brains.
which unwanted cell parts are degraded by cellular machinery, apparently plays
a role in pruning. Sulzer said that in animal models, activating a protein,
mTOR, that inhibits macroautophagy resulted in abnormally dense synapses and
autistic-type behaviors. The brains of autistic patients similarly have
increased levels of mTOR, and a surplus of damaged cellular components, such as
mitochondria, that are normally eliminated by macroautophagy.
A number of genetic
mutations linked to autism apparently increase mTOR activity, he said. When animals genetically engineered to overexpress
mTOR were given a drug to inhibit the protein in adolescence, it reactivated macroautophagy
and normalized autism-like behaviors.
Although the specific drug may not be appropriate, “this
is very promising clinically,” said Sulzer, because the finding suggests that
“during the process of active pruning [several years after autism symptoms
typically appear] it may not be too late to treat these children.”