CB1 Receptor Knockouts Have An Accelerated Cognitive Decline

Study finds that CB1 receptor knockout mice have increased brain inflammation, which leads to earlier cognitive decline.

Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1?/?), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1?/? mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1?/? mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation. (via.)

Bacteria playing their part in autism, diagnostic opportunity

“Gut bacteria may contribute to autism”

Children with autism appear to have a characteristic chemical signature in their urine which might form the basis of an early diagnostic test for the condition.

The finding also adds weight the hypothesis that substances released by gut bacteria are contributing to the onset of the condition.

Autism has previously been linked to metabolic abnormalities and gastrointestinal problems such as gut pain and diarrhoea. Several studies have also hinted at changes in gut bacteria in the faeces of children with autism. [...]

Using nuclear magnetic resonance (NMR) spectroscopy to analyse the children’s urine, they found that each of these groups had a distinct chemical fingerprint, with clear and significant differences between children with autism and unrelated controls.”The signature that comes up is related to gut bacteria,” says Nicholson. It is not yet clear whether the bacteria’s metabolic products contribute to the development of autism, but it is a possibility worth investigating, he adds. A large proportion of autistic children have severe gastrointestinal problems that tend to appear at about the same time as the behavioural symptoms.

“It adds another link to the gut bacterial involvement in the onset of disorder,” says Glenn Gibson of the University of Reading, UK, who has previously identified abnormally high levels of clostridium bacteria in children with autism.

One possibility is that the gut bacteria in children with autism are producing toxins that might interfere with brain development. One of the compounds identified in the urine of autistic children was N-methyl-nicotinamide (NMND), which has also been implicated in Parkinson’s disease.

Meanwhile, Derrick MacFabe of the University of Western Ontario in London, Canada, and his colleagues have found that short-chain fatty acids produced by clostridium bacteria can induce reversible autism-like behavioural and biochemical changes in rats. [...]

Even if bacteria are not actually contributing to the observed metabolic changes, they could still be put to use. “There is probably the basis of a test for autism based on a urinary metabolic profile,” says Nicholson. (via: 1,2.)

Shouts out to Dale for sharing this interesting link with me.

“Exhaustion Syndrome” & Depression

Certain personality traits heighten susceptibility to psychiatric disorders. Therefore a research team at Umeå University wanted to study whether this patient group had any susceptibility factors that could explain the development of their disorder. The patient group is distinguished by being anxious and pessimistic, with a weak sense of self, which is common in many psychiatric disorders. What was special about this group was that they stood out as persistent, ambitious, and pedantic individuals.

Being ambitious, fastidious, and overachieving also appears to make a person more prone to exhaustion syndrome. According to Agneta Sandström’s dissertation, individuals with exhaustion syndrome demonstrate impaired memory and attention capacity as well as reduced brain activity in parts of the frontal lobes. Regulation of the stress hormone cortisol is also impacted in the group, with altered sensitivity in the hypothalamic-pituitary-adrenal axis (HPA axis). [...]

The HPA axis in the patient group shows reduced sensitivity in the pituitary, with less secretion of adrenocorticotropic hormone (ACTH) following stimulation with corticotropin (CRH), as well as heightened sensitivity in the adrenal cortex, with increased release of cortisol in relation to the amount of ACTH secreted. There is also a difference in the diurnal rhythm of cortisol, with the patients presenting a flatter secretion curve than the other two groups. The researchers could not detect any reduction in the volume of the hippocampus in the patient group. The proportion of individuals with measurable levels of the pro-inflammatory cytokine interleukin 1 is higher in the patient group. (via.)

What’s BDNF & substance p got to do with eczema?

Per Wikipedia BDNF is…

BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.

So I ran across this little interesting tidbit that I’ll want to follow up on later, if I happen to remember to. That is that apparently elevated levels of BDNF and Substance P (involved in nociception/pain perception) is involved in eczema? Per Substance P’s Wikipedia:

High levels of BDNF and Substance P have been found associated with increased itching in eczema.[27][28]

Interestingly also, apparently naked mole rats lack substance p altogether.

Totally unrelated, but also unusual… BDNF is found to be increased after prolonged seizure activity.

Schizophrenia & immune activation

Researchers at the Swedish medical university Karolinska Institutet have discovered that patients with recent-onset schizophrenia have higher levels of inflammatory substances in their brains. [...]

Scientists at Karolinska Institutet have now been able to analyse inflammatory substances in the spinal fluid of patients with schizophrenia, instead of, as in previous studies, in the blood. The results show that patients with recent-onset schizophrenia have raised levels of a signal substance called interleukin-1beta, which can be released in the presence of inflammation. In the healthy control patients, this substance was barely measurable. [...]

“We would have made terrific progress if we were one day able to treat schizophrenia patients with immunotherapy, as it might then be possible to interrupt the course of the disease at an early stage of its development,” says Professor Engberg. (via.)

Stress-related Gene (MKP-1 or MKP1), Depression, and Heat Stress

Duman’s team did whole genome scans on tissue samples from 21 deceased individuals who had been diagnosed with depression and compared gene expression levels to those of 18 individuals who had not been diagnosed with depression. They found that one gene called MKP-1 was increased more than two-fold in the brain tissues of depressed individuals.

This was particularly exciting, say the researchers, because the gene inactivates a molecular pathway crucial to the survival and function of neurons and its impairment has been implicated in depression as well as other disorders. Duman’s team also found that when the MKP-1 gene is knocked out in mice, the mice become resilient to stress. When the gene is activated, mice exhibit symptoms that mimic depression.

The finding that a negative regulator of a key neuronal signaling pathway is increased in depression also identifies MKP-1 as a potential target for a novel class of therapeutic agents, particularly for treatment resistant depression. (via.)

Interesting tidbits from elsewhere:

ACC (Anterior Cingulate Cortex) & Asthma Words

Researchers used functional magnetic resonance imaging (fMRI) to scan the brains of six mildly asthmatic people who were asked to inhale ragweed or dust-mite extracts.

Subjects were then shown three types of words: asthma-related (such as “wheeze”), non-asthma negative (such as “loneliness”) and neutral (such as “curtains”). Shortly after, researchers measured lung function in the subjects as well as molecular signs of inflammation in their sputum.

The fMRI scans revealed that the asthma-related terms stimulated robust responses in two brain regions–the anterior cingulate cortex and the insula–that were strongly correlated with measures of lung function and inflammation. The other types of words were not strongly associated with lung function or inflammation.

The two brain structures are involved in transmitting information about the physiological condition of the body, such as shortness of breath and pain levels, says Davidson, and they have strong connections with other brain structures essential in processing emotional information. (via.)

Heightened immune response in socially anxious

Everyone experiences social stress, whether it is nervousness over a job interview, difficulty meeting people at parties, or angst over giving a speech. In a new report, UCLA researchers have discovered that how your brain responds to social stressors can influence the body’s immune system in ways that may negatively affect health.

Lead author George Slavich, a postdoctoral fellow at the UCLA Cousins Center for Psychoneuroimmunology, and senior author Shelley Taylor, a UCLA professor of psychology, show that individuals who exhibit greater neural sensitivity to social rejection also exhibit greater increases in inflammatory activity to social stress. [...]

The researchers recruited 124 individuals — 54 men and 70 women — and put them into two awkward social situations. First, in the lab, the volunteers completed the Trier Social Stress Test (TSST), which involves preparing and delivering an impromptu speech and performing difficult mental arithmetic, both in front of a socially rejecting panel of raters wearing white lab coats. Mouth swabs were taken before and after the public-speaking tasks to test for changes in two key biomarkers of inflammatory activity — a receptor for tumor necrosis factor-? (sTNF?RII) and interleukin-6 (IL-6).

In a second session, 31 of the participants received an MRI brain scan while playing a computerized game of catch with what they believed were two other real people. The researchers focused on two areas of the brain known to respond to social stress — the dorsal anterior cingulate cortex (dACC) and the anterior insula.

At first, the game was between all three “players.” Halfway through the game, however, the research subject was excluded, leading to an experience of social rejection. The researchers then examined how differences in neural activity during social rejection correlated with differences in inflammatory responses to the TSST.

Their results showed that individuals who exhibited greater neural activity in the dorsal anterior cingulate cortex and anterior insula during social rejection in the brain scanner also exhibited greater increases in inflammatory activity when exposed to acute social stress in the lab.

“This is further evidence of how closely our mind and body are connected,” Slavich said. “We have known for a long time that social stress can ‘get under the skin’ to increase risk for disease, but it’s been unclear exactly how these effects occur. To our knowledge, this study is the first to identify the neurocognitive pathways that might be involved in inflammatory responses to acute social stress.” [...]

One critical question raised by the present findings is why neural sensitivity to social rejection would cause an increase in inflammation. There are several possible reasons, the authors note. For one, since physical threats have historically gone hand in hand with social threat or rejection, inflammation may be triggered in anticipation of a physical injury. Inflammatory cytokines — proteins that regulate the immune system — are released in response to impending (or actual) physical assault because they accelerate wound-healing and reduce the risk of infection.


This may also be of interest: Tylenol (acetaminophen) eases social anxiety.