Archive for the ‘Neuroscience’ Category

#SfN13: Day 1

Today I had the treat of meeting Garrett Smith, a fellow North Carolinian, here from Davidson College in Davidson, NC (less than an hour from where I grew up! and where my sister-in-law currently works as an adjunct assistant biology professor). I planned on visiting his poster when I saw it dealt with medial septum (MS), a brain structure that I'm very interested in, and I was not disappointed.

Garrett was kind enough to guide me through his research: the MS provides excitatory cholinergic and inhibitory GABAergic inputs to the dentate gyrus (DG). In addition, a major input to the DG comes from the ipsilateral entorhinal cortex (EC) through the perforant path. There are also a small number of DG connections from the contralateral EC, but apparently not enough to cause depolarization to threshold in the DG (as measured by population spikes in the DG when the contralateral EC is stimulated).

All this changes when the ipsilateral EC is lesioned. Without the perforant path input, something signals the MS and the contralateral EC to form more synapses with the DG. The added input allows the contralateral EC, when stimulated, to provide inputs resulting in population spikes in the DG.

What Garrett's group found was that stimulating the MS shortly before stimulating the contralateral EC significantly increased the size of the population spike evoked from EC stimulation. This indicates that the MS could be involved in the recovery of learning and memory following an ipsilateral EC lesion in rodents by strengthening the contralateral EC input to the DG. What role exactly this plays in vivo is unknown, though it is compelling, as all these structures are involved in learning and memory.

The mechanism by which the MS achieves this potentiating effect is also unknown, but they plan on investigating it in future studies by studying how the DG responds to cholinergic and GABAergic inputs individually.

It was a good day, and I'm excited for tomorrow!

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Blogging at #SfN13

Good news! Between overeating and enjoying the sunny California weather, I will be writing daily posts from Saturday, November 9th, to Wednesday, November 13, as an official blogger for this year's annual Society for Neuroscience meeting! Specifically, my posts will focus on neural excitability and novel methods and technology development, though I may throw in some other things as well. I look forward to it! So stay tuned...

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Consciousness

The Scarecrow from The Wizard of OzThe cerebellum, the part of the brain that deals with motor learning, is a structure that makes up about 10% of the volume of the brain. It has many, many, tiny neurons in it, so much so that it actually contains more neurons than the rest of the brain. Interestingly, if the cerebellum is removed from someone's head, although they will have motor deficits, their personality and conscious experience of the world will remain unchanged. In contrast, even though the cerebrum has less neurons than the cerebellum, removal of the cerebrum will leave a person in a permanent, vegetative, and unconscious state. Something about the cerebrum that scientists haven't quite pinned down yet is responsible for conscious, subjective experience. I recently watched an excellent discussion among experts from different fields about the nature of consciousness, where they brought up this very point. I highly recommend the video, if only to see neuroscientist Christof Koch's fabulous shirt.

Although consciousness is difficult to define, much less explain, neuroscientists have made a lot of interesting progress in this area in recent years. It makes neuroscience an exciting field to be a part of, and is one of the things that drew me to neuroscience in the first place. What makes it so intriguing is its mystique--consciousness is one of the most scientifically intractable questions of which I know. It is easy enough to explain the neural mechanisms of something such as the tuning of an individual neuron in the visual cortex, but it is another thing entirely to explain what neural basis there is, if any, for the subjective experience of sight.

Neuroscience often teaches us to view the brain in terms of action potentials. Sodium atoms rush into the cell, potassium atoms rush out, causing a transient change in the local voltage. That's what the brain is: different types of atoms moving around in response to different forces. Harmonizing this deterministic, mechanical, soulless view of the brain with the idea of a subjective experience of consciousness is a difficult task. How can a large number of atoms moving around cause consciousness?

Christof Koch put it this way in an interview on NPR:

"So we know the brain is part of the physical universe, just like anything else. But brains - human brains, animal brains, baby brains - brains also exude this stuff, this feeling, like feelings of pain or pleasure, of artistic sensibility, of seeing red.

"And the big mystery has always been, how is it that a physical system that's described by the laws of physics, how can it give rise to conscious sensation? And can other physical systems such as a computer, can they also give rise to physical sensation? Is it something in the structure, is it something in the information, is it something in the complexity of it that gives rise to consciousness?"

He and another scientist, Giulio Tononi, are advocates of the idea that consciousness is a product of something called integrated information. As the name suggests, this theory borrows concepts from information theory and applies them to neuroscience, emphasizing that the integration of information across brain regions and modalities is critical to consciousness. They talk about this theory some in another video here.

Other scientists have recently developed alternative metrics for measuring consciousness. Traditionally, scientists observed electrical patterns recorded from EEG electrodes and then attempted to correlate them with behavioral manifestations of consciousness or unconsciousness, leading to some technologies such as the bispectral index, or BIS monitor used by many anesthesiologists to measure a patient's depth of anesthesia.

Recent studies using EEG have even found heightened signs of consciousness in rats for a short period of time immediately following death. This surprising result came when scientists found high levels of gamma rhythm synchronization between the front and back of the brain. Synchronous activity in the gamma frequency range is thought to be responsible for binding information from different brain regions together to make a coherent experience. However, it is important to remember that these studies do not measure consciousness directly, but rather measure electrical and behavioral correlates of consciousness.

Researchers in Italy and Giulio Tononi also came up with a new metric for measuring consciousness, called the perturbational complexity index, or PCI. Their metric also relies on EEG to measuring different large-scale electrical rhythms in the brain, and was developed by measuring these rhythms in people during a wide variety of different states of consciousness. Although they were able to distinguishing between different states of consciousness in test subjects using only their analysis of the subjects' EEG signals, many more people would need to be tested before this method became clinically relevant.

Yet other researchers have different theories about the nature of consciousness. Some postulate that quantum effects in the brain could explain consciousness. For instance, some have proposed that electrons in structural proteins called microtubules would be a possible candidate for information processing through quantum effects, allowing the brain to perform quantum computer-like calculations. There is even some evidence that microtubules are involved in anesthesia, which could lend support to this hypothesis, but many scientists feel this theory lacks substantial evidence.

Whatever the physical substrates of consciousness are, it will definitely be interesting to see where this field goes in the next few years. What do you think is the basis for consciousness? How should we measure it?

Anesthetics Change the Intrinsic Excitability of Neurons

Gamma oscillations in the brain are hypothesized to be involved in consciousness (Gray, 1994). Interestingly, general anesthetics are known to change both the incidence and frequency of gamma oscillations in the hippocampus. They are also known to increase the amplitude and decay time-constant of postsynaptic inhibitory currents (Whittington et al., 1996). No causal relationship, however, has been established between these network effects and cellular effects. In an effort to begin this description, I have measured the frequency-current relationships in CA1 pyramidal cells both under control conditions and in the presence of the anesthetic propofol.

Methods:

Using the whole-cell patch-clamp method, I delivered a series of input currents to the neurons. Whole-cell patch-clamp is a method where a finely-tipped glass micropipette is filled with an artificial intracellular fluid and brought down to the surface of a cell. Negative pressure (sucking) allows the cell to form a seal with the pipette and rupture the section of membrane just under the pipette tip. The intracellular fluid of the cell becomes continuous with the artificial intracellular fluid contained in the pipette. An electrode is inserted into the back end of the pipette, which can be used to record from and manipulate the cell electrically.

Each cell received the current steps with and then without the anesthetic drug propofol.

Results:

The most significant result that I saw was a change in the gain of the neuron (as evidenced by a change in the slope of the f-I curve) in response to propofol. I recorded the firing rates of the neurons in response to increasing steps of currents (current steps are shown in Figure 1).

Figure 1. Current steps.

Firing rates were separated into initial rates (rate during the first 0.3 seconds of pulse times) and steady-state rates (rate during the last third of pulse times). For this study, I was most interested in the steady-state firing rates. First, I recorded the f-I curves from neurons first without and then with propofol added (Figure 2; n=9). The process took about 30 minutes. There was a modest change in the gain of the neurons in response to the propofol treatment.

Figure 2. Steady-state f-I curve for the control (blue) and with the addition of propofol (red).

However, as I was doing the experiments I noticed that the gain of the neuron would change over time, independent of the addition of propofol. Therefore, I wanted to eliminate the effects of time from my analysis of the effects of propofol. I again followed the same protocol as I did for Figure 1, but without adding propofol for the second f-I curve. This second recording I called a "delayed control" (Figure 3; n=10). Here I also noticed a change in gain, but in the opposite direction.

Figure 2. Steady-state f-I curve for the control (blue) and delayed control (red).

When I compared the gain of the neurons with propofol added with the delayed recordings without propofol, significant differences were seen (Figure 4; p=0.021, unpaired t-test).

Figure 4. Bar graph of changes in gain (slope) as a result of the addition of propofol.

This is indicative of a change in the intrinsic excitability of the neurons as a result of the propofol treatment. This change in intrinsic neuronal excitability may, in addition to the synaptic effects of propofol, lead to changes in network behavior and contribute to propofol-induced anesthesia.

The entire poster for this study can be seen here: Utah BME 2011 Conference Poster.

References

Gray, CM (1994). Synchronous oscillations in neuronal systems: mechanisms and functions. Journal of Computational Neuroscience, 1(1-2), 11–38.

Whittington, MA, Jefferys, JG, & Traub, RD (1996). Effects of intravenous anaesthetic agents on fast inhibitory oscillations in the rat hippocampus in vitro. British Journal of Pharmacology, 118(8), 1977–86.