Tag Archives: neuroscience

Cognitive disorders: the role of dendritic spines.

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Neuronal plasticity:

A major contribution of neuroscience to the humanities is the knowledge that the structure of the brain is moulded by the experiences the mind goes through – the phenomenon known as plasticity. It means that the circuits of the brain are sculpted by habitat, schooling, language, relationships, and culture, as well as by the unfolding genetic programme. The action occurs below the micrometre scale – at synapses (the points of connection between neurons) – and involves the exquisite choreography of a number of molecular machines. These molecular processes are so fundamental for cognition that their failure (whether driven by gene mutation or by harsh environments) results in neuropsychological disability. A major locus of plasticity (and hence, cognitive disability) is the dendritic spine.

pyramidal neuron

The dendrites of pyramidal neurons express thousands of dendritic spines. P=pyramidal neuron.

Principal neurons in the brain, such as cortical pyramidal neurons, express tens of thousands of small protruberances on their dendritic trees. These structures (dendritic spines) receive excitatory information from other neurons, and are highly dynamic. They can adjust their responsiveness to glutamate (the major excitatory neurotransmitter), becoming stronger (potentiation) or weaker (depression), as local circumstances dictate. This strengthening (LTP) or weakening (LTD) can be transient, or persist over long periods and as such, serves as an ideal substrate for learning and memory at synapses and in circuits. Potentiated spines increase in size, and express more AMPA glutamate receptors, whilst the opposite pattern occurs in synaptic depression to the extent that spines can be 'absorbed' back into the dendritic tree.

Over the course of childhood, dendritic spines (excitatory synapses) increase in number, but their numbers are 'pruned' back during adolescence to reach a plateau. Enriched environments have been shown to increase spine density, impoverished environments the opposite. In common psychiatric disorders, spine density is altered. For example, the most robust histological finding in schizophrenia is a reduction of spine density in the frontal cortex, auditory cortex and the hippocampus. In major depression, spines (and dendrites) are lost in the hippocampus. In autism, spine density actually increases. Finally, in Alzheimer's and other dementias there is a catastrophic, and progressive loss of cortical and sub-cortical spines.

Regulation of the spine:

The molecular biology of dendritic spines involves hundreds of proteins, but the outlines are now reasonably well understood. Scaffolding proteins [such as PSD95, shank(s), AKAP, stargazin and homer(s)] provide structural support and provide orientatation for membrane bound receptors, ion-channels and their downstream signalling pathways. The scaffold (post-synaptic density), facilitates effective signalling by ensuring that the correct protein partners are in close apposition. The scaffold is also tethered to proteins which bridge the synaptic cleft (cell adhesion molecules) and to bundles of actin filaments which provide the structure and force for spine enlargement (and retraction).

dendritic spine

Spine plasticity is fundamental for learning and memory. The shuttling of AMPA receptors underlies early phase plasticity. Modification of the actin cytoskeleton and local protein synthesis underlie long term plastic changes.

There is a constant remodelling of the actin cytoskeleton within the spine in response to synaptic and network signalling. Remodelling is via small, cytoplasmic G-proteins from the RHO family. Some family members promote the growth and stabilisation of actin filaments, whereas others promote actin disassembly. Mutations in the proteins which regulate actin dynamics are a cause of learning disability. Finally local protein synthesis (and degradation) occurs within dendritic spines, is tightly controlled and is essential for plasticity. Abnormalities in local protein synthesis within the spine underlie learning disability syndromes such as fragile X, neurofibromatosis and tuberous sclerosis.

Spine pathology:

Recent years have seen glutamate synapses move to centre stage in neuropsychiatry. This is not surprising given the role of pyramidal neurons (glutamate containing neurons) in information processing, and the role of glutamate transmission in learning and memory [see link]. But it is remarkable that so many psychological and cognitive disorders appear to 'coalesce' at dendritic spines.

The enclosed vector-graphic image [click here] highlights a selection of some of the proteins which are now known to be involved in autism, learning disability and schizoprenia.

Research will continue to decipher the complexity (and beauty) of the dendritic spine, but potential treatments are starting to emerge for disorders like fragile X, (which until recently were thought to be not amenable for drug treatment, as was the case for schizophrenia until the 1950s). Molecular neuroscientists will, almost certainly, continue to uncover more treatment targets. The task for psychiatry, as ever, is to keep abreast of neuroscience in all it's complexity (and beauty).

 

BD or not BD?

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The Bipolar Spectrum: can brain scans resolve diagnostic uncertainty?

The concept of manic-depression was extended some years back to cover less extreme manifestations characterised by hypomania (Bipolar II), as well as the classical form, defined by mania (Bipolar I). But other forms (perhaps less dramatic, though still a cause of much suffering) also exist.

These ‘softer’ forms of bipolar illness appear to blur into unipolar depression and perhaps also with the category which has been termed, borderline personality disorder. Although there has been a trend to view psychiatric disorders as points on a spectrum, rather than as discrete, encapsulated diagnoses, many psychiatrists would hesitate to equate borderline personality disorder and bipolar illness. Ultimately the matter will be resolved when we fully grasp the underlying neurobiology of affective disorders.

A new paper from researchers based in Sydney provides an authoritative and balanced account of the current state of our knowledge. The authors elegantly summarise the functional MRI literature across the hypothesised spectrum. One feature appears to be common across the various disorders – limbic hyperactivity. Perhaps this is not so surprising as the limbic system is the ‘seat’ of emotion, and all the various disorders/forms are characterised by emotional upset.

But there also appear to be differences. For example, the orbitofrontal cortex (a higher centre, which ‘dampens’ and regulates emotion) appears to be underactive in bipolar I, but not in unipolar depression nor in borderline personality disorder.

Further work will be needed before clear-cut conclusions can be drawn. The authors conclude…”Eventually, as the respective signatures of personality-based emotional dysregulation and bipolar mood dysregulation become increasingly crisp, we may be able to use functional neural profile to assist in clarifying diagnosis or treatment options in clinically muddy presentations, although a great deal of work will need to be done before imaging will be sufficiently robust to be used in this manner.”

The full paper can be read here:

http://www.expert-reviews.com/doi/pdfplus/10.1586/ern.12.126

 

New insights into how antidepressants work.

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fMRI scan.

It is well established that antidepressants take at least 2 weeks to shift a depressed mood. A new study from researchers at Oxford, reveals that the drug is working behind the scenes, much earlier than this.

People with depression are known to show an exaggerated response to pictures of human faces that are expressing fear. The response can be observed using functional MRI brain scanning. The part of the brain which lights up is their own 'fear processor', the amygdala. The usual interpretation is that the depressed patient's fear system is unduly sensitive to anything from the outside world which signifies fear. And human faces elicit the most robust response.

Previous work had shown that standard SSRI antidepressants can dampen down the hyperactive amygdala, and return it's function to normal. What was unknown was whether the effect on the amygdala or the effect on mood came first.

The Oxford researchers have now shown that SSRI antidepressants dampen down the amygdala at least 1 week before the patient experiences a shift in their mood. They compared 3 groups of people: depressed patients who had been randomised to receive escitalopram (10mg); depressed patients who had been randomised to placebo; and a group of healthy controls. A week after being randomised to active drug or placebo, the depressed patients were given an fMRI scan.

The main finding was that the patients who had been taking escitalopram for a week had normal amygdala responses to pictures of fearful human faces. In contrast, the patients on placebo showed the characteristic hyperactive response in the amygdala on the right hand-side of their brains (see scan above). Notably, 1 week was too early for any antidepressant effect – Treated and untreated patients were equally depressed at this stage.

This is an important finding, which shows that SSRI antidepressants affect how the brain processes emotional information before the patient feels an improvement in their mood.

Further studies are planned. One key goal will be to assess if the degree of amygdala dampening at 1 week can distinguish between patients who ultimately get better from those who will remain depressed. The technology might even be used in selecting the 'best' type of antidepressant drug for a particular patient, rather than having to adopt a 'wait and see' approach.

The full paper can be read here

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488813/

 

Major Depression: What is currently known?

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“About one in five people will suffer from major depression at some point in their lives. Aside from the psychological burden, people suffering from depression are known to be at higher risk of heart disease”.

But what are the causes of depression? What happens in the brain when someone is depressed? And which treatments work best?

Writing in the Lancet, Phillips and colleagues from the University of Pittsburgh give an authoritative account of the current state of the art. They appraise the evidence for antidepressant drugs and psychological therapies, and highlight promising new treatment strategies.

Kupfer DJ, Frank E & Phillips ML (2012) Major depressive disorder: new clinical, neurobiological and treatment perspectives. Lancet 379:1045-55.

The full article is available at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397431/