Drug development efforts for late-onset Alzheimer disease (AD) have met with disappointing results. Krstic and Knuesel argue for a re-evaluation of pathological mechanisms underlying the disease, with a shift of focus away from amyloid-β as the key therapeutic target. Through integration of their own research with the wider literature, they present a model that places inflammation and impairments in axonal functions and integrity at the heart of AD pathology. Dimitrije Krstic & Irene Knuesel Nature Reviews Neurology 9, 25-34 (January 2013) | doi:10.1038/nrneurol.2012.236
Synapses and receptive fields of the cerebral cortex are plastic. However, changes to specific inputs must be coordinated within neural networks to ensure that excitability and feature selectivity are appropriately configured for perception of the sensory environment. The authors induced long-lasting enhancements and decrements to excitatory synaptic strength in rat primary auditory cortex by pairing acoustic stimuli with activation of the nucleus basalis neuromodulatory system.
Here they report that these synaptic modifications were approximately balanced across individual receptive fields, conserving mean excitation while reducing overall response variability. Decreased response variability should increase detection and recognition of near-threshold or previously imperceptible stimuli. They confirmed both of these hypotheses in behaving animals. Thus, modification of cortical inputs leads to wide-scale synaptic changes, which are related to improved sensory perception and enhanced behavioral performance.
Robert C Froemke, et al.
A new study published November 20 in the open-access journal PLOS Biology has identified hundreds of small regions of the genome that appear to be uniquely regulated in human neurons. These regulatory differences distinguish us from other primates, including monkeys and apes, and as neurons are at the core of our unique cognitive abilities, these features may ultimately hold the key to our intellectual prowess (and also to our potential vulnerability to a wide range of 'human-specific' diseases from autism to Alzheimer's).
The eye is an extension of the CNS in terms of its development and anatomy, and in terms of its dialogue with the immune system. Many neurodegenerative disorders of the brain and spinal cord have manifestations in the eye, which are often evident before the emergence of clinical neurological symptoms. London et al. highlight how investigation of the eye represents a noninvasive approach to the detection and diagnosis of neurodegenerative disorders, and discuss how eye research could provide a valuable model to study CNS disorders.
The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, the authors sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here they develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), they observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal’s decision to act in a challenging situation. Surprisingly, they next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behavior.
Given the unprecedented tools that are now available for rapidly comparing genomes, the identification and study of genetic and genomic changes that are unique to our species have accelerated, and we are entering a golden age of human evolutionary genomics. Here the authors provide an overview of these efforts, highlighting important recent discoveries, examples of the different types of human-specific genomic and genetic changes identified, and salient trends, such as the localization of evolutionary adaptive changes to complex loci that are highly enriched for disease associations. Finally, they discuss the remaining challenges, such as the incomplete nature of current genome sequence assemblies and difficulties in linking human-specific genomic changes to human-specific phenotypic traits.