Archive for the ‘Frontal cortex’ Category

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Joseph LeDoux‘s book, “Synaptic Self: How Our Brains Become Who We Are” opens with his recounting of an incidental glance at a t-shirt, “I don’t know, so maybe I’m not” (a play on Descartes’ cogito ergo sum) that prompted him to explore how our brain encodes memory and how that leads to our sense of self.  More vividly, Elizabeth Wurtzel, in “Prozac Nation” recounts, “Nothing in my life ever seemed to fade away or take its rightful place among the pantheon of experiences that constituted my eighteen years. It was all still with me, the storage space in my brain crammed with vivid memories, packed and piled like photographs and old dresses in my grandmother’s bureau. I wasn’t just the madwoman in the attic — I was the attic itself. The past was all over me, all under me, all inside me.” Both authors, like many others, have shared their personal reflections on the fact that – to put it far less eloquently than LeDoux and Wurtzl – “we” or “you” are encoded in your memories, which are “saved” in the form of synaptic connections that strengthen and weaken and morph through age and experience.  Furthermore, such synaptic connections and the myriad biochemical machinery that constitute them, are forever modulated by mood, motivation and your pharmacological concoction du jour.

Well, given that my “self” or “who I think of as myself” or ” who I’m aware of at the moment writing this blog post” … you get the neuro-philosophical dilemma here … hangs ever so tenuously on the biochemical function of a bunch of tiny little proteins that make up my synaptic connections – perhaps I should get to know these little buggers a bit better.

OK, how about a gene known as kalirin – which is named after the multiple-handed Hindu goddess Kali whose name, coincidentally, means “force of time (kala)” and is today considered the goddess of time and change (whoa, very fitting for a memory gene huh?).  The imaginative biochemists who dubbed kalirin recognized that the protein was multi-handed and able to interact with lots of other proteins.  In biochemical terms, kalirin is known as a “guanine nucleotide exchange factor” – basically, just a helper protein who helps to activate someone known as a Rho GTPase (by helping to exchange the spent GDP for a new, energy-laden GTP) who can then use the GTP to induce changes in neuronal shape through effects on the actin cytoskeleton.  Thus, kalirin, by performing its GDP-GTP exchange function, helps the actin cytoskeleton to grow.  The video below, shows how the actin cytoskeleton grows and contracts – very dynamically – in dendrites that carry synaptic spines – whose connectivity is the very essence of “self”.  Indeed, there is a lot of continuing action at the level of the synapse and its connection to other synapses, and kalirin is just one of many proteins that work in this dynamic, ever-changing biochemical reaction that makes up our synaptic connections.

In their paper”Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes” [doi: 10.1073/pnas.0904636106] Michael Cahill and colleagues put this biochemical model of kalirin to the test, by examining a mouse whose version of kalirin has been inactivated.  Although the mice born with this inactivated form are able to live, eat and breed, they do have significantly less dense patterns of dendritic spines in layer V of the frontal cortex (not in the hippocampus however, even though kalirin is expressed there).  Amazingly, the deficits in spine density could be rescued by subsequent over-expression of kalirinHmm, perhaps a kalirin medication in the future? Further behavior analyses revealed deficits in memory that are dependent on the frontal cortex (working memory) but not hippocampus (reference memory) which seems consistent with the synaptic spine density findings.

Lastly, the authors point out that human kalirin gene expression and variation has been associated with several neuro-psychiatric conditions such as schizophrenia, ADHD and Alzheimer’s Disease.   All of these disorders are particularly cruel in the way they can deprive a person of their own self-perception, self-identity and dignity.  It seems that kalirin is a goddess I plan on getting to know better.  I hope she treats “me” well in the years to come.

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Pyramidal cell -  A human neocortical pyramida...
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Among the various (and few) significant results of recent landmark whole-genome analyses (involving more than 54,000 participants) on schizophrenia (covered here and here), there was really just one consistent result – linkage to the 6p21-22 region containing the immunological MHC loci.  While there has been some despair among professional gene hunters, one man’s exasperation can sometimes be a source of great interest and opportunity for others – who – for many years – have suspected that early immunological infection was a key risk factor in the development of the disorder.

Such is the case in the recent paper, “Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats” by Baharnoori et al., [doi: 10.1016/j.schres.2008.10.003].  In this paper, the authors point out that Emil Kraepelin, who first described the disorder we now call schizophrenia, had suggested that childhood inflammation of the head might be an important risk factor.  Thus, the immunopathological hypothesis has been around since day 0 – a long time coming I suppose.

In their research article, Baharnoori and colleagues have taken this hypothesis and asked, in a straightforward way, what the consequences of an immunological challenge on the developing brain might look like.  To evaluate this question, the team used a Sprague-Dawley rat model and injected pregnant females (intraperitoneally on embryonic day 16) with a substance known as lipopolysaccharide (LPS) which is known to mimic an infection and initiate an immune response (in a manner that would normally depend on the MHC loci found on 6p21-22). Once the injections were made, the team was then able to assess the consequences to various aspects of brain and behavior.

In this paper, the team focused their analysis on the development of the frontal cortex and the hippocampus – 2 regions that are known to function poorly in schizophrenia.  They used a very, very focused probe of development – namely the overall shape, branching structure and spine formations on pyramidal cells in these regions – via a method known as Golgi-Cox staining.  The team presents a series of fantastically detailed images of single pyramidal cells (taken from postnatal day 10, 35 and 60) from animals who’s mothers were immunologically challenged and those who were unexposed to LPS.

Briefly, the team finds that the prenatal exposure to LPS had the effect of reducing the number of dendritic spines (these are the aspects of a neuron that are used to make synaptic connections with other neurons) in the developing offspring.  Other aspects of neuronal shape were also affected in the treated animals – basically amounting to a less branchy, less spiny – less connectable – neuron.  If that’s not a basis for a cognitive disorder than what else is?  Indeed, the authors point out that such spines are targets – in early development – for interneurons that are essential for long-range gamma oscillations that help distant brain regions function together in a coherent manner (something that notably does not happen in schizophrenia).

Thus, there is many a reason (54,000 strong) to want to better understand the neuro-immuno-genetic-developmental mechanisms that can alter neuronal structure.  Exciting progress in the face of recent genetic setbacks!

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Few genes have been studies as intensely as apolipoprotein E (APOE).  In particular, one of its variants, the epsilon-4 allele has been especially scrutinized because it is correlated with an earlier onset (about 10 years earlier than average) of Alzheimer’s Disease.  Among the many roles of APOE – its just a tiny cholesterol binding protein – are those as participant in synaptic plasticity, early neural development, damage-response and other processes – all of which share the need for the synthesis and movement of neuronal membranes (see the fluid mosaic model) and their component parts – such as cholesterol.   Hence, whenever neural membranes are being synthesized (plasticity & development) or damaged (overstimulation and other sources of oxidative damage) the tiny APOE is there to help with its membrane stabilizing cholesterol molecule in hand. Over the course of a lifetime, routine damage to neuronal membranes adds up (particularly in the hippocampus where constant storage-recall memory functions place enormous demands on synaptic plasticity systems), and individuals (such as epsilon-4 carriers) may simply show more wear-and-tear because their version of APOE is not as optimal as the other forms (epsilon-2 and -3).

apoeWith this etiological model in mind, perhaps you would like to take better care of you cell membranes (much like your car mechanic implores to change your car’s spark plugs and oil to keep the engine clean on the inside).  Moreover, perhaps you would like to do-so especially if you knew that your APOE system was less optimal than average.  Indeed, results from the recent REVEAL study suggest that folks who are in their 50’s are not unduly distressed to make this genetic inquiry and find out their genotypic status at this APOE polymorphism – even though those who discovered that they were epsion-4 carriers reported more negative feelings, understandably.  Still, with a number of education and intervention strategies available, an optimistic outlook can prevail.

Furthermore, there are ever newer diagnostic strategies that can improve the rather weak predictive power of the genetic test.  For example, cognitive assessments that measure hippocampal-dependent aspects of memory or visual orienting have been shown to be valid predictors of subsequent dementia – even moreso in populations that carry the APOE epsilon-4 allele.  Other forms of neuroimaging that directly measure the structure and function of the hippocampus also have tremendous sensitivity (here for a broad review of imaging-genetics of AD) and can, in principle, provide a more predictive view into one’s distant future.

On the very cutting edge of this imaging-genetic crystal ball technology, lies a recent paper entitled, “Distinct patterns of brain activity in young carriers of the APOE-e4 allele” by Fillippini and colleagues [doi: 10.1073/pnas.0811879106].  Here, the research team asks whether individuals in their late 20’s show structural/functional brain differences that are related to APOE genotype.  They employ various forms of imaging analysis such as a comparison of brain activity when subjects were performing a novel vs. familiar memory task and also an analysis of so-called resting state networks – which reflect a form of temporal coherence (brain areas that oscillate in-sync with each other when subjects are lying still and doing nothing in the scanner).  For the analysis of the memory task, the team found that APOEe4 carriers showed more activation in the hippocampus as well as other brain regions like the anterior midbrain and cerebellum.  When the team analysed a particular resting state network – the default mode network – they found differences in the medial temporal lobe (containing head of the hippocampus and amygdala) as well as the medial prefronal cortex.  According to the paper, none of these differences could be explained by differences in the structure or resting perfusion of the young-adult brains in the study.

Wow, these results seem to suggest that decades before any mild cognitive impairments are observable, there are already subtle differences in the physiology of the APOEe4 brain – all of which could be detected using the data obtained in 6 minutes of rest. 6 minutes of rest and spit in a cup – what does the future hold?

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Amidst a steady flow of upbeat research news in the behavioral-genetics literature, there are many inconvenient, uncomfortable, party-pooping sentiments that are more often left unspoken.  I mean, its a big jump – from gene to behavior – and just too easy to spoil the mood by reminding your colleagues that, “well, everything is connected to everything” or “that gene association holds only for that particular task“.  Such may have been the case often times in the past decade when the so-called imaging-genetics literature emerged to parse out a role for genetic variation in the structure and functional activation of the brain using various neuroimaging methods.  Sure, the 5HTT-LPR was associated with amygdala activation during a face matching task, but what about other tasks (and imaging modalities) and other brain regions that express this gene.  How could anyone (let alone NIMH) make sense out of all of those – not to mention the hundreds of other candidate genes poised for imaging-genetic research?

With this in mind, it is a pleasure to meet the spoiler-of-spoilers! Here is a research article that examines a few candidate genetic polymorphisms and compares their findings across multiple imaging modalities.  In his article, “Neural Connectivity as an Intermediate Phenotype: Brain Networks Under Genetic Control” [doi: 10.1002/hbm.20639] Andreas Meyer-Lindenberg examines the DARPP32, 5HTT and MAOA genes and asks whether their associations with aspects of brain structure/function are in any way consistent across different neuroimaging modalities.  Amazingly, the answer seems to be, yes.

For example, he finds that the DARPP32 associations are consistently associated with the striatum and prefrontal-striatal connectivity – even as the data were collected using voxel-based morphometry, fMRI in separate tasks, and an analysis of functional connectivity.  Similarly, both the 5HTT and MAOA gene promoter repeats also showed consistent findings within a medial prefrontal and amygdala circuit across these various modalities.

This type of finding – if it holds up to the spoilers & party poopers – could radically simplify the understanding of how genes influence cognitive function and behavior.  As suggested by Meyer-Lindenberg, “features of connectivity often better account for behavioral effects of genetic variation than regional parameters of activation or structure.”  He suggests that dynamic causal modeling of resting state brain function may be a powerful approach to understand the role of a gene in a rather global, brain-wide sort of way.  I hope so and will be following this cross-cutting “connectivity” approach in much more detail!

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One of the difficulties in understanding mental illness is that so many aspects of mental life can go awry – and its a challenge to understand what abnormalities are directly linked to causes and what abnormalities might be consequences or later ripples in a chain reaction of neural breakdown.  Ideally, one would prefer to treat the fundamental cause, rather than only offer palliative measures for symptoms that arise from tertiary neural inefficiencies. In their research article entitled, “Evidence That Altered Amygdala Activity in Schizophrenia Is Related to Clinical State and Not Genetic Risk“, [doi: 10.1176/appi.ajp.2008.08020261] (audio link) Rasetti and colleagues explore this issue.

Specifically, they focus on the function of the amygdala and its role in responding to, and processing, social and emotional information.  In schizophrenia, it has been found that this brain region can be somewhat unresponsive when viewing faces displaying fearful expressions – and so, the authors ask whether the response of the amygdala to fearful faces is, itself, an aspect of the disorder that can be linked to underlying genetic risk (a type of core, fundamental cause).

To do this, the research team assembled 3 groups of participants: 34 patients, 29 of their unaffected siblings and 20 demographically and ethnically matched control subjects.  The rationale was that if a trait – such as amygdala response – was similar for the patient/sibling comparison and dissimilar for the patient/control comparison, then one can conclude that the similarity is underlain by the similarity or shared genetic background of the patients and their siblings.  When the research team colected brain activity data in response to a facial expression matching task performed in an MRI scanner, they found that the patient/sibling comparison was not-similar, but rather the siblings were more similar to healthy controls instead of their siblings.  This suggests that the trait (amygdala response) is not likely to be directly related to core genetic risk factor(s) of schizophrenia, but rather related to apsects of the disorder that are consequences, or the state, of having the disorder.

A follow-up study using a different trait (prefrontal cortex activity during a working memory task) showed that this trait was similar for the patient/sibling contrast, but dissimilar for the patient/control contrast – suggesting that prefrontal cortex function IS somewhat linked to core genetic risk.  Congratulations to the authors on this very informative study!

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Neuregulin 1Image via Wikipedia Nowadays, as many folks peer into the vast tangled thicket of their own genetic code, they, as I, assuredly wonder what it all means and how best to ascertain their health risks. One core theme that emerges from repeated forays into one’s own data is that many of us carry a scads of genetic risk for illness, but somehow, find ourselves living rather normal, healthy lives. How can this be ? A recent example of this entails a C/T snp (c) located in the 5′ flanking region of the neuregulin 1 gene which has been repeatedly associated with schizophrenia. Axel Krug and colleagues recently reported in their paper, “Genetic variation in the schizophrenia-risk gene neuregulin1 correlates with differences in frontal brain activation in a working memory task in healthy individuals” that T/C variation at this snp is associated with activation of the frontal cortex in healthy individuals. Participants were asked to keep track of a series of events and respond to a particular event that happened “2 events ago” . These so-called n-back tasks are not easy for healthy folks, and demand a lot of mental focus – a neural process that depends heavily on circuits in the frontal cortex. Generally speaking, as the task becomes harder, more activity in the frontal cortex is needed to keep up. In this case, individuals with the TT genotype seemed to perform the task while using somewhat less activity in the frontal cortex, rather than the risk-bearing CC carriers. As someone who has tried and failed to succeed at these tasks many times before, I was sure I would be a CC, but the 23andMe data show me to be a non-risk carrying TT. Hmmm … maybe my frontal cortex is just underactive.

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PhotoImage via Wikipedia Like most parents, I enjoy watching my children develop and marvel at the many similarities they bear to myself and my wife. The reshuffling of physical and behavioral features is always a topic of discussion and is the definitive icebreaker during uncomfortable silences with the inlaws. In some cases, the children are blessed with the better traits, but in other cases, there’s no option but to cringe when, “Look – wow, he really has your nose – hmmm”, is muttered. Most interesting, is the unfolding of patterns of behavior that unfold slowly with age. Differences in temperament and personality can instill great pride in parents but also can be a grating source of friction. One of my F1’s has recently taken to sessions of shrill, spine rattling, screaming which I hope will pass soon.

Why ? Many parents ask. “Have WE been raising him/her to do this ? – surely that’s what the neighbors must think”. “Is it something in the family ? I heard Aunt Marie was a bit of a screamer as a child – hmmm.”

In one of several of their landmark studies on the genetic regulation of pediatric brain development, Jay Giedd and colleagues, now provide in their recent paper, “Variance Decomposition of MRI-Based Covariance Maps Using Genetically-Informative Samples and Structural Equation Modeling”, a core framework on the relative contribution of genes vs. environment for the developing cortex. The paper is part of an ongoing longitudinal study of pediatric brain development at the Child Psychiatry branch at NIMH. Some 600 children participated – including identical twins, fraternal twins, siblings and singleton children.

The team used an analytical approach known as MACAAC (Mapping Anatomical Correlations Across the Cerebral Cortex) to ask how much does the variation in a single part of the brain co-vary with other parts ? Then the team used structural equation modeling to explore how much this co-variation might differ across identical twins vs. fraternal vs. siblings vs. age-matched singleton children. In locations where there is an high genetic contribution to co-variation in cortical thickness, identical twins should co-vary more tightly than fraternal twins or siblings etc. In this way, the team were able to parse out the relative influence of genes vs. environment to the developing brain.

In general terms, the team reports that a single genetic factor accounts for the majority of variation in cortical thickness, which they note may be consistent with a major mechanism of development of cortical layers involving the migration of neurons along radial glia. Genetic co-variances across separate locations in the brain were highest in the frontal cortex, middle temporal gyrus and left supramarginal gyrus. Interestingly, when environmental covariations were observed, they were usually restricted to just one hemisphere, while genetic covariations were often observed bilaterally.

Figure 5 of this paper is really incredible, it shows which areas of the cortex are more influenced by genes vs. environment. If I can just find the areas involved in screaming, the next time one of my neighbors looks askance at my F1, I’ll be able to explain.

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