New findings in aging, pain, depression, suicide, anxiety and schizophrenia

In vitro neurogenesis assay: from aging markers to intervention trials. Dr Chiara De Lucia (King’s College London, London, UK)

A hippocampal progenitor line model has been used to confirm that markers of apoptosis and aging can be upregulated when these cells are exposed to serum from older adults compared to plasma from younger adults. Several other biomarkers of aging also showed variation under these conditions.¹

Adult neurogenesis may be associated with lifestyle factors

Dr de Lucia’s work with this model showed an association between genes from nutrient-sensing pathways (e.g., NAMPT, FOXO3A and GRB10) and markers of neurogenesis.² By replicating aging by repeatedly passaging cells, she also showed upregulation in similar genes. With these in vitro results in mind, an epidemiological study in volunteers of a paired associates learning (PAL) task dependent on hippocampal function was carried out. This revealed that participant lifestyle factors, including diet and physical activity, moderated the association between PAL scores and the expression of GRB10 and another nutrient-sensing pathway gene, SIRT1.

Oxytocin improves positive emotional valence to painful stimuli via action in the insular cortex. Ms Stephanie Küppers (Ruprecht-Karis-Universität Heidelberg, Heidelberg, Germany)

Hypothalamic paraventricular nucleus (PVN) oxytocin neurons widely project throughout the brain and are involved in physical and emotional components of pain processing.³ Ms Küppers’ work investigated the insular cortex that also projects to a number of brain regions and is involved in pain. Using retrograde adeno associated viruses injected into the rat brain, she found that PVN oxytocin neurons can project to the insular cortex. The oxytocin receptor in the insular cortex was found to be primarily located in GABAergic interneurons.

Positive emotional valence to a painful stimulus can be improved by oxytocin release in the insular cortex

Pain sensitivity in a rat following an inflammatory injection to the paw can be assessed via time spent in the chamber where the painful stimulus was given. Usual decreases in this time are lessened in rats when oxytocin neurons are stimulated. Also tested during neuronal stimulation was pain threshold to a measured pinch with tweezers. This did not decrease, thus suggesting, said Ms Küppers, that oxytocin release leads to a reduction in pain perception but not pain levels. Using an operant conditioning chamber, Ms Küppers also showed that if a rat trained to lever press to gain a reward additionally receives a mild shock, the number of times it will press the lever despite this is higher when the oxytocin neurons are stimulated. These findings tie in with previous work showing that the insular cortex is involved in valance memorisation and retention and that insular cortex lesions lead to alterations in sensory valence but not perception.⁴

Cognitive deficits in major depressive disorder are associated with alterations in the structural network of the brain. Mr Marius Gruber (Institute for Translational Psychiatry, University of Münster, Münster, Germany)

Cognitive deficits can occur in major depressive disorder (MDD). These may be due to decreased interaction between brain networks, which, in patients with MDD, is correlated with disease severity.^5,6 In Mr Gruber’s laboratory, structural and diffusion weighted magnetic resonance imaging (MRI) images are used to reproduce white matter tracts and produce connectivity matrices (‘connectomes’).⁷

Cognition-related network connectivity is reduced in patients with major depressive disorder

To test the hypotheses that patients with MDD have alterations in cognitive performance associated with connectome subnetworks, 805 healthy controls were compared to patients with remitted (n=372) or acute (n=307) MDD. Cognitive performance, assessed via verbal fluency, processing speed and verbal learning and memory tests, was lower in the patients with MDD. By assessing ‘cognition-related networks,’ Mr Gruber and colleagues identified structural networks associated with each of the three cognitive performance domains. In patients with MDD, especially in acute patients, connectivity strength was reduced. They also found an increase in symptom severity associated with decreased cognitive performance and connectivity strength.

Implicating the nitric oxide system in the nurture-nature debate: nitric oxide synthase genetic variant, childhood maltreatment and onset of suicidal behaviours. Dr Aiste Lengvenyte (Department of Emergency Psychiatry and Acute Care, CHU Montpelier, Montpelier, France)

Nitric oxide (NO) is a neuromodulator with a role in memory consolidation. In times of acute stress, nitric oxide synthase (NOS) activity in the hippocampus and prefrontal cortex (PFC) increases. In chronic unpredictable stress, there are decreased levels of NOS in the hypothalamus and decreased cardiac NO production.^8-12 It is not known if there is a direct relationship between brain and plasma levels of NO/NOS and MDD. However, in patients with MDD, there are fewer NOS containing neurons in these memory and stress related regions, the hippocampus and hypothalamus respectively, and increased levels of plasma NO have been found in people who have attempted suicide.^13-16

A positive association between a nitric oxide synthase 3 polymorphism and early suicidality in people with a history of childhood abuse was detected

Dr Lengvenyte investigated associations between childhood trauma, NOS genotypes and age of onset of suicidal behaviours. Her study included 414 patients (74.5% female) with at least one suicide attempt. An association was found between a NOS 3 polymorphism (wild genotype BB) and age of onset of suicide attempt. In people who had experienced childhood abuse, having the BB genotype increased the likelihood of dying by suicide when added to early attempts (<18 years old), multiple attempts, family history of suicidal behaviours and severe suicide attempts. This was compared to people who had not experienced abuse plus had b/b genotype in all cases and, in some cases (multiple attempts, family history, early attempts) also those who only had b/b genotype. Associations were robust when adjusted for age, sex, psychiatric diagnosis, mood stabiliser treatment, eating disorder and substance use disorder. The effect was additive as opposed to interactive.

Sex dependent effects of early-life microbiota depletion on behaviour, neuroimmune function and neuronal development. Ms Caoimhe Lynch (APC Microbiome Institute, University College Cork, Cork, Ireland)

A number of studies have investigated how the gut microbiota can influence neurodevelopment and behaviour.^17-19 These suggest, according to Ms Lynch, that there is a “critical window of microbial influence on neurodevelopmental outcomes.” She used a murine model where the microbiota was depleted postnatally, pre-weaning or post-weaning using antibiotics. This led to differences in microbial richness and composition compared to non-depleted mice, including increases in potentially pathogenic bacterium and decreases in those that produce short chain fatty acids. Also found were changes in neuroactive compounds, such as those involved in acetate, kynurenine, inositol and glutamate synthesis.

Early gut microbiota depletion in females may influence anxiety-like behaviour in adolescence

At all timepoints, antibiotic treated mice had changes in amygdala microglia morphology. There was also a decrease in short chain fatty acid producers, which were speculated by Ms Lynch to have a role in their microglia findings. Additionally alterations in myelin gene expression in the PFC were found. This especially occurred when microbiota depletion was carried out in the pre-weaning timepoint in females. These mice also displayed more anxiety-like behaviour in adolescence and, to a lower extent, adulthood, though the latter was not significant.

Subchronic amisulpride administration induces negative symptoms and reduces reward activation in healthy individuals). Dr Martin Osugo (King’s College London, London, UK)

Dopamine receptor antagonist antipsychotics may be associated with metabolic syndrome factors, such as weight gain, and negative symptoms of schizophrenia, such as sedation.^20,21 Such adverse events may be due to dopamine-related reward circuit disruption. For instance, those related to monetary reward are associated with the cingulate cortex, medial frontal cortex and striatum²² and those related to food processing are associated with the amygdala, orbital frontal cortex and insula.²³

Antipsychotic action on dopamine receptors may lead to increased high calorie food preference and decreased reward gaining pleasure

To ascertain whether circuit disruption is due to schizophrenia or antipsychotic medication, Dr Osugo administered amisulpride (400 mg), a selective dopamine D2 and D3 antagonist, or placebo to 25 volunteers (60% female) for 1 week in a crossover manner with ≥10 days washout. During functional MRI imaging, volunteers were shown pictures of high or low calorie foods or non-food images. There was an increase in activation to high calorie food in the amisulpride group compared to the placebo in the PFC, anterior cingulate cortex (ACC), gustatory cortex and paracingulate. A computerised monetary incentive task involved anticipation and receipt of a reward. The amisulpride group showed significantly reduced activation compared to placebo during this task in the PFC, ACC, insula and caudate. Significant increases were also shown on Brief Negative Symptom Scale scores compared to baseline and placebo.