This study was focused on assessing the usefulness of optogenetic techniques for exploring brain circuitry and, in particular, the thalamocortical and corticothalamic circuits including the thalamic reticular nucleus. In that regard the study found the techniques to be very useful and, in particular, they showed that shining laser light onto the axon terminals of neurons expressing Channelrhodopsin-2 could be excited and release neurotransmitter.
For the most part, the research team confirmed earlier observations about circuit connectivity and dynamics from experiments that used other techniques. Nevertheless, there were some novel observations. Most surprising was that they never saw inhibitory synaptic activity between neurons in the thalamic reticular nucleus.
Noise in synaptic inputs reduces the reliability of neural responses. However, when noise is strongly correlated between inhibitory and excitatorysynapses, fluctuations in inhibitory synaptic input may cancel corresponding fluctuations in excitatorysynaptic input. Strongly correlated noise may arise if the excitatory and inhibitory pathways originate from a common source. The result would be to reduce variability in a neuron’s spike output and increase the reliability of the signal.
To measure the covariation of excitatory and inhibitorysynaptic input required Dr. Cafaro and Dr. Rieke to measure the two conductances as near to simultaneously as possible. The results showed that excitatory and inhibitory input to retinal ganglion cells do indeed covary. Then they recorded from directionally selective retinal ganglion cells while stimulating the retina with a bar of light moved in different directions. The results showed that the signal processing underlying directional selectivity depends on covariation of excitatory and inhibitorysynaptic inputs, which resulted in greater direction selectivity.
A new review of processes underlying Alzheimer’s disease by Dr. Karl Herrup presents a new synthesis and framework to view this debilitating illness. The current standard view of the cause of Alzheimer’s disease is known as the Amyloid Cascade Hypothesis. The existence of amyloid beta plaques in the brains of Alzheimer’s disease patients lead to the idea that the plaques may be the cause of the disease (see my earlier blog post “Wrong Idea for Cause of Alzheimer’s Disease?“).
Dr. Herrup presents a compelling argument for an Age-Based Hypothesis to explain the cause of Alzheimer’s disease. This hypothesis takes into account a lot of new data that the Amyloid Cascade Hypothesis does not. In addition, the amyloid deposition cycle is taken into account and fits in naturally within the larger framework of the Age-Based Hypothesis.
Age, of course, is considered a fundamental factor in the Age-Based Hypothesis. You may break your hip at any age but as you age a broken hip is made more likely (due to poor balance at an advanced age, for instance) and more serious because of age related changes in the healing power of the body among other factors. The brain in the aged is different in many ways from the youthful brain. The Age-Based Hypothesis states that, given an elderly brain, the process leading to the expression of Alzheimer’s disease follows three important steps. Each step is highlighted in a light blue bubble in Figure 1 (above) and sequentially numbered in purple.
First an initiating injury transforms an elderly brain into an elderly brain on a trajectory towards expressing Alzheimer’s disease. The injury could be anything from a serious bump on the head to a highly traumatic event such as the loss of a spouse. The initiating injury leads to the second step which is chronic nervous tissue inflammation. This is where the Age-Based Hypothesis encompasses amyloid beta deposition since inflammation of brain tissue activates the amyloid deposition cycle. In the third step, the chronically inflamed brain tissue moves into a new state (change-of-state) that may kick off any of several intracellular molecular cascades that lead to synaptic dysfunction and neuronal death. It’s synaptic dysfunction and neuronal death that result in dementia.
The Age-Based Hypothesis makes a lot of sense and may lead to new insights including new ways of treating the disease. There may be many changes to this hypothesis over the coming months and years but I think it’ll prove to be a productive hypothesis.
