Fast-spiking interneurons and the critical period

How do children learn to play instruments and speak languages so much easier than adults, and why does brain damage result in worse outcomes in the mature brain vs. the young brain?  These questions are central to the study of how “critical periods” are regulated in the brain.


Electron micrograph from a single 70 nm cross-section through a fast-spiking parvalbumin-containing (gold labeling = white dots) presynaptic terminal forming a synapse (red dots) with a pyramidal soma. Original colors are inverted, contours have been raised and membranous structures are highlighted in aqua for ease of visualization. Presynaptic vesicles (colored ovals) within perisomatic fast spiking terminals mostly cluster within ∼200 nm of the synapse, with a few close enough (≤2 nm) to be deemed docked.

Critical periods in brain development define temporal windows when neuronal physiology and anatomy are most sensitive to changes in sensory input or experience (e.g. sound, touch, light, etc.).  The maturation of inhibitory cells that release the neurotransmitter GABA, especially a subset called fast-spiking (FS) interneurons, is thought to gate this period of neuronal ‘plasticity’ in the mammalian primary visual cortex.  However, it has remained unclear what aspects of FS cell development are important for permitting this period of neuronal malleability in the visual cortex. A new paper in Journal of Neuroscience from the Turrigiano lab addresses the question.

To explore how FS cell development might be linked to critical period plasticity, Brandeis postdoc Marc Nahmani and Professor Gina Turrigiano employed a well-established assay for cortical plasticity in visual cortex called monocular deprivation (MD), and measured FS cell connections using confocal and electron microscopy, as well as optogenetic stimulation of the FS cell population (i.e. shining light onto FS cells possessing light-gated channels to make them fire action potentials).

Following up on previous work from the Turrigiano lab (Maffei et al., 2006), they found that MD induces a coordinated increase in FS interneuron to pyramidal cell (the major excitatory output cells of the cortex) pre- and postsynaptic strength.  These changes occur if MD is performed during, but not before the critical period in visual cortex, suggesting they may play a role in gating this period of heightened neuronal plasticity.  Future studies are aimed at determining the timeline for these changes across the extent of the critical period in visual cortex.

see: Nahmani M, Turrigiano GG (2014) Deprivation-Induced Strengthening of Presynaptic and Postsynaptic Inhibitory Transmission in Layer 4 of Visual Cortex during the Critical Period. Journal of Neuroscience 34:2571-2582.

How seeing can change what you see

We sometimes take it for granted how the way we see enables us to perceive and interact with the world, but how our visual system works is amazing. It’s an intricately choreographed process – from the light that comes into our eyes, to the way that our brains carry that information and form it into an image we can understand. If brain cells are improperly connected during growth and development, or if part of the system is destroyed by injury, all kinds of visual havoc can be a result. But how does a brain get wired properly in the first place?

 In a paper in the Journal of Neuroscience last week, Professor Steve Van Hooser’s lab reported some of the effects of experience on development. The new paper shows evidence that neurons in all layers of the visual cortex aren’t just ‘born’ with the right connections between the parts of the brain that control vision. According to their data, the act of seeing itself makes changes in how the neurons process visual information. The lab is continuing their studies of brain circuits to uncover how, during development, the act of seeing changes how you see.
Clemens JM, Ritter NJ, Roy A, Miller JM, and Van Hooser SD. The Laminar Development of Direction Selectivity in Ferret Visual Cortex. J. Neurosci. 12 December 2012, 32(50): 18177-18185. 

Michael Stryker to deliver Pepose Vision Sciences Award Lecture on March 12

This year’s Pepose Award in Vision Sciences, funded by an endowment from Brandeis graduates Jay Pepose (’75) and his wife, Susan Feigenbaum (’74), will be awarded to Michael Stryker, the William Francis Ganong Professor of Physiology at UCSF.  Dr. Stryker, who has been a faculty member at ‘SF since 1978, has been at the forefront of vision research for decades.  His lab has used a variety of animal models to probe cortical development and plasticity in the visual system, and developed a variety of techniques to analyze and measure these changes, often resulting in images that are visually inspiring in their own right (Figure, below).

This top down view of cat visual cortex shows color coded orientation columns, using a continuous-periodic imaging paradigm developed in the Stryker lab.

As a postdoc at Harvard Medical School, Dr. Stryker worked with Nobel Laureates Torsten Wiesel and David Hubel, whose groundbreaking research using the visual cortex of cats provided a first glimpse into cortical organization, development, and plasticity.  By studying how the responsiveness of neurons in visual cortex changes as a result of visual deprivation, Hubel and Wiesel pioneered a model for developmental neurobiology and introduced us to concepts like ocular dominance, orientation columns, and critical periods, a foundation upon which Dr. Stryker has built much in the subsequent decades: describing the arrangement of orientation maps in pinwheels; probing the role of spontaneous retinal activity in producing these maps; highlighting the importance of ongoing developmental activity using visual deprivation and pharmacological activity blockades; and more recently examining the molecular substrates of these changes using the genetically accessible murine model.  His career spans the visual field from its foundational work to the most modern, and with no end in sight!

Join us on March 12, 3:45 pm in Gersetnzang 121 as he accepts the award and delivers a public lecture on “Rewiring the Brain: Mechanisms of Competition and Recovery of Function in the Mammalian Cortex“.

What spontaneous neural activity reveals about the brain

You look at a photograph of a hiker in an alpine landscape. The hiker, her dog, the trees in the background, and the houses of a village in the distance are vividly reconstructed by your brain from the shades of light and color on the paper. The subjects of the picture are so distinct and clear that it is hard to see how difficult it was for your visual system to reconstruct it. A closer examination highlights some of the problems our brain has to overcome: The hiker in the foreground is higher and occupies a larger area than the houses and the trees in the background, yet you perceive her as being smaller. The dog is partially hidden by one of the legs of its master, yet you perceive it as a single animal, rather than two half-dogs. Theoretical models and psychological experiments led researchers to think that, in these examples and in countless other everyday situations, your brain makes use of an internal model of the world, built over a lifetime of experiences, to correctly interpret the image.

By analyzing the mathematical equivalents of the internal model, researchers in Jozsef Fiser’s lab in the Volen Center for Complex Systems at Brandeis and colleagues at Cambridge University (UK) deduce that, if the internal model works as hypothesized by theoreticians, traces of its functioning would be seen in neural activity recorded in complete darkness. Intuitively, an internal model would use its understanding of typical natural images to “fill-in” noisy and incomplete parts of a visual scene. As the brightness of an image is reduced, the visual system increasingly relies on prior expectations, until most of the neural activity is dominated by the internal model. This intuition is compatible with previous observations of neural data showing strong and coordinated activity in the visual system in the absence of visual stimulation, whose significance had remained unexplained.

Figure 1: The two panels show the distribution of all possible instantaneous activity patterns on 16 electrodes, in response to natural movies (M, x-axis) and during spontaneous activity in the dark (S, y-axis). Colors represent the number of electrodes detecting activity in each pattern, as shown in the legend on the left. In a young ferret, just after eye opening, the frequency with which the patterns occur is very different in the two conditions (left panel); instead, for an adult animal of about 4 months of age, the two distributions are very similar, as indicated by the patterns clustering around the diagonal.

In a paper published this week in Science, the authors analyzed neural activity in the primary visual cortex of ferrets watching natural scenes or artificial patterns, or just sitting in darkness. They found that, as predicted by the model, when the animal is in darkness the recorded patterns of neural activity closely resemble those recorded in response to natural visual scenes, but not those recorded in response to artificial stimuli. The fact that the similarity was specific to natural scenes indicates that the neural activity was due to the model’s expectations about the environment, and not to some other secondary effects. The authors repeated the measurements on animals at different stages of development, and found that the match of neural activity in the dark and in natural images was not present at birth, but rather gradually developed over the first four months of visual experience, as the internal model adapted to the statistics of the external world.

These results provide neural evidence for the internal models theorized by computational neuroscientists, and allow us to take a glance at the computations performed by the visual areas of the brain.

Visually driven intrinsic plasticity

In mammals including humans, proper development of the cortex is heavily dependent on sensory experience. Neurons in sensory cortex are subject to a “use it or lose it” rule, whereby if they are deprived of sensory input during a critical period of development, they lose the ability to respond altogether. This loss of responsiveness could occur through synaptic changes (synaptic plasticity), or through changes in the intrinsic ability of neurons to fire action potentials (intrinsic plasticity).

Up until now experience-dependent development has largely been ascribed to  synaptic plasticity mechanisms.  In the cover article in this week’s issue of Neuron, (Nataraj et al., Neuron 68, 750–762, November 18, 2010), Brandeis postdocs Kiran Nataraj, Nicolas Le Roux, Marc Nahmani and Sandrine Lefort from the lab of Professor Gina Turrigiano show that a form of intrinsic plasticity termed “long-term potentiation of intrinsic excitability”, or LTP-IE, plays an important role in experience-dependent refinements of cortical circuits. This study shows that sensory drive normally keeps cortical output neurons active by triggering LTP-IE, and sensory deprivation reduces the ability of these neurons to fire by preventing the activation of this form of plasticity. This suggests that LTP-IE serves a “use it or lose it” function in cortical output neurons, gating cortical output by keeping active neurons responsive, while suppressing the output of  inactive neurons.

How regions of the brain get their specificity

The cortex is divided into functionally distinct regions, and the layers of the visual cortex are a classic example. But how much do the intrinsic electrical properties of a particular neuron type vary from region to region? In a recent paper in J. Neurosci., Brandeis Neuroscience graduate students Mark Miller and Ben Okaty together with Prof. Sacha Nelson found a new region-specific firing type in Layer 5 pyramidal neurons. They argue that features as basic as membrane properties can be region-specific, and that this regional specialization of circuitry contributes to the determination of the region’s functional specialization.

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