Neurogenesis of pain and depression in the hippocampus

Amazing stuff!

"Chronic pain and depression are mutually linked. Ding et al. explored the mechanistic link between chronic pain and depression in humans and rodents ... In patients and an animal model, early stages of chronic pain were found to be associated with an increase in hippocampal volume, whereas later stages were associated with decreased hippocampal volume.

These changes in rats were followed by the development of depressive-like behavior. Mechanistically, the authors showed that microglial activation leads to dysregulation of hippocampal neurogenesis (producing volumetric changes), shifts in hippocampal physiology, and onset depressive-like behaviors. The study provides valuable insights into the role of the hippocampus in the development of comorbid depression in the context of chronic pain."

From the abstract of the Perspective:

"Pain is classically defined as a sensory experience, yet it also engages emotional and cognitive processes. When pain becomes chronic—persists or recurs beyond 3 months from injury—it is frequently accompanied by disability and emotional dysregulation. Among these comorbidities, depression, anxiety, and sleep disorders are the most prevalent, yet the mechanistic relationships linking pain chronicity to these affective consequences remain poorly understood. On page 1235 and 1236 of this issue, Wei et al. (3) and Ding et al. (4), respectively, report evidence of pain-related brain regulation at two opposite ends of the temporal spectrum. Wei et al. describe a neural circuit that accounts for daily fluctuations in pain sensitivity. Meanwhile, Ding et al. identify cellular and structural brain changes that contribute to the emergence of depression in chronic pain. These observations offer new insight into how chronic pain becomes coupled to affective and cognitive comorbidities."

From the abstract:

"Structured Abstract

INTRODUCTION

Chronic pain is a leading risk factor for depression and anxiety, yet the brain mechanisms that convert persistent sensory distress into affective dysfunction remain unclear. Neuroimaging studies have implicated the hippocampus in both pain and mood regulation, but it is unknown whether hippocampal alterations precede, accompany, or result from the emergence of affective symptoms. Resolving this temporal and mechanistic relationship is essential for explaining individual vulnerability to depression in chronic pain and for identifying intervention points that can prevent this transition.

RATIONALE

We hypothesized that chronic pain induces a staged remodeling process, rather than a uniform degenerative change, within the hippocampus. Specifically, we proposed that the dentate gyrus serves as a critical gate where persistent nociceptive input is initially accommodated through adaptive plasticity but later diverted into maladaptive circuit destabilization by interactions between adult-born neurons and microglia.

RESULTS

Integrating longitudinal human neuroimaging data from the UK Biobank with rodent models of neuropathic pain, we identified a conserved biphasic trajectory of hippocampal remodeling. During early stages of chronic pain, hippocampal volume increased and hippocampal-dependent cognitive performance improved, consistent with an adaptive response. As pain persisted, this phase transitioned to hippocampal atrophy, cognitive decline, and the emergence of anxiety- and depression-like behaviors.

At the cellular level, early chronic pain selectively increased activity of newborn neurons within the dentate gyrus and triggered targeted recruitment and remodeling of microglia in the neurogenic niche. These cell-type–specific changes progressively amplified local circuit excitability and disrupted network balance, marking a transition from adaptive hippocampal plasticity to maladaptive circuit remodeling. Functionally, distinct modes of dentate gyrus modulation produced divergent outcomes: Suppressing newborn neuron activity alleviated affective symptoms but impaired cognition, whereas microglial modulation prevented anxiety- and depression-like behaviors while preserving cognitive function. Together, these findings identify microglia as a key regulator of the pain-to-depression transition.

CONCLUSION

By resolving distinct modes of dentate gyrus modulation, we show that microglia act as critical and therapeutically tractable regulators of the transition from chronic pain to affective disorders. Our findings reveal that this transition is governed not by hippocampal hyperactivity per se but rather by microglia-dependent remodeling that determines whether adaptive plasticity is sustained or diverted into maladaptive circuit states. Targeting microglial activation preserves hippocampal structure and cognitive function while preventing affective pathology, positioning microglia as a selective leverage point for interrupting the progression from chronic pain to mood disorders."

In Science Journals | Science

Pain across time (Perspective, no public access)

From chronic pain to depression: Neurogenesis-driven microglial remodeling in the hippocampal dentate gyrus (no public access)

Genetic overlap of 14 psychiatric disorders explains why patients often have multiple diagnoses

Good news! Amazing stuff!

"An international collective of researchers is delivering new insights into why having multiple psychiatric disorders is the norm rather than the exception. In a study ... the team provides the largest and most detailed analysis to date on the genetic roots shared among 14 conditions. ..."

"... The majority of people diagnosed with a psychiatric disorder will ultimately be diagnosed with a second or third disorder in their lifetime, creating challenges for defining and treating these conditions. While a person’s environment and lived experience influence their risk for developing multiple disorders, their genetic makeup can also play a significant role.

By analyzing data from over 6 million individuals, the working group mapped the genetic landscape of 14 psychiatric conditions and revealed five families of disorders with high levels of genetic overlap. The results mark an important step toward understanding the genetic connections among psychiatric disorders and could ultimately help clinicians better serve their patients. ..."

"Psychiatric disorders display high levels of comorbidity and genetic overlap, challenging current diagnostic boundaries. For disorders for which diagnostic separation has been most debated, such as schizophrenia and bipolar disorder, genomic methods have revealed that the majority of genetic signal is shared.

While over a hundred pleiotropic loci have been identified by recent cross-disorder analyses, the full scope of shared and disorder-specific genetic influences remains poorly defined.

Here we addressed this gap by triangulating across a suite of cutting-edge statistical and functional genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders (1,056,201 cases).

Using genetic association data from common variants, we identified and characterized five underlying genomic factors that explained the majority of the genetic variance of the individual disorders (around 66% on average) and were associated with 238 pleiotropic loci.

The two factors defined by (1) Schizophrenia and bipolar disorders (SB factor); and (2) major depression, PTSD and anxiety (Internalizing factor) showed high levels of polygenic overlap and local genetic correlation and very few disorder-specific loci.

The genetic signal shared across all 14 disorders was enriched for broad biological processes (for example, transcriptional regulation), while more specific pathways were shared at the level of the individual factors.

The shared genetic signal across the SB factor was substantially enriched in genes expressed in excitatory neurons, whereas the Internalizing factor was associated with oligodendrocyte biology.

These observations may inform a more neurobiologically valid psychiatric nosology and implicate targets for therapeutic development designed to treat commonly occurring comorbid presentations."

Genetic overlap of 14 psychiatric disorders explains why patients often have multiple diagnoses

Study reveals genetic overlap of 14 psychiatric disorders, explaining why patients often have multiple diagnoses (original news release) "Co-led by VCU expert Kenneth Kendler, a global research group has developed the most comprehensive genetic map to date, revealing five families of disorders with high levels of overlap."

Mapping the genetic landscape across 14 psychiatric disorders (open access)

Fig. 1: Genome-wide structural models.

a, Heatmap of rgs across the 14 disorders ... Disorders that load on the same factor are shown in the same colour. Per the legend at the bottom of the panel, darker blue shading indicates larger, positive rgs. LDSC estimates were used as the input to genomic SEM to produce the results in b and c. b, Estimates from the five-factor model along with standard errors in parentheses. Estimates are standardized relative to SNP-based heritabilities, where this is equal to the sum of the squared factor loading (the single-headed arrow(s) from the factor to the disorder) and the residual variance (the values on the double-headed arrows on the single-colour circles with text labels that begin with u). Disorders are shown as pie charts; the proportion of residual variance is shaded in purple and the variance explained by the psychiatric factors is shaded in the colour of the corresponding factor. c, Standardized estimates from the p-factor model. The disorders are colour coded as in b, and the first-order factors (F1–F5) are also colour coded to show variance explained by the second-order p-factor in yellow.