Hippocampal neuropathology in suicide: Gaps in our knowledge and opportunities for a breakthrough

Zhang, Lin; Lucassen, Paul J.; Salta, Evgenia; Verhaert, Peter; Swaab, D.F.

doi:10.1016/j.neubiorev.2021.12.023

Cited by 14 publications

(6 citation statements)

References 187 publications

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“…BDNF has different biological effects, such as preventing neuronal damage and death, improving neuronal pathological state, and promoting neuron regeneration. Recent studies have shown that elevated glucocorticoid levels impaired the BDNF expression in the hippocampus [ 45 , 46 , 47 , 48 , 49 , 50 ]. However, our data demonstrated the opposite results where the lower CS levels were associated with higher BDNF mRNA expression levels in the hippocampus of low-anxiety rats.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical Anxiety Level Reduction in Animal Chronic Stress: A Unique Role of Hippocampus Neurobiology

Tseĭlikman

Akulov

Shevelev

et al. 2022

IJMS

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A paradoxical reduction in anxiety levels in chronic predator stress paradigm (PS) in Sprague–Dawley rats has recently been shown in previous works. In this paper, we studied the possible neurobiological mechanism of this phenomenon. We segregated PS-exposed Sprague–Dawley rats into the high- and low-anxiety phenotypes. The long-lasting effects of PS on corticosterone levels, blood flow speed in the carotid arteries, diffusion coefficient, and 1H nuclear magnetic resonance spectra in the hippocampus were compared in the high-anxiety and low-anxiety rats. In addition, we evaluated the gene BDNF expression in the hippocampus which is considered to be a main factor of neuroplasticity. We demonstrated that in low-anxiety rats, the corticosterone level was decreased and carotid blood flow speed was increased. Moreover, in the hippocampus of low-anxiety rats compared to the control group and high-anxiety rats, the following changes were observed: (a) a decrease in N-acetyl aspartate levels with a simultaneous increase in phosphoryl ethanol amine levels; (b) an increase in lipid peroxidation levels; (c) a decrease in apparent diffusion coefficient value; (d) an increase in BDNF gene expression. Based on these findings, we proposed that stress-induced anxiety reduction is associated with the elevation of BDNF gene expression directly. Low corticosterone levels and a rise in carotid blood flow speed might facilitate BDNF gene expression. Meanwhile, the decrease in apparent diffusion coefficient value and decrease in N-acetyl aspartate levels, as well as an increase in the lipid peroxidation levels, in the hippocampus possibly reflected destructive changes in the hippocampus. We suggested that in Sprague–Dawley rats, these morphological alterations might be considered as an impetus for further increase in neuroplasticity in the hippocampus.

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Section: Discussionmentioning

confidence: 99%

Paradoxical Anxiety Level Reduction in Animal Chronic Stress: A Unique Role of Hippocampus Neurobiology

Tseĭlikman

Akulov

Shevelev

et al. 2022

IJMS

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“…We investigated a network linked to suicidality, which was mediated by a mini neurocircuit in the hippocampus, and a major circuit involving the hypothalamus and PFC. Our discovery of a specific group of hippocampal granule cells exclusively associated with fatal suicidality indicates that the DG may contain cellular and molecular signatures for intense and determined suicidal ideations 35 . Importantly, this suicidespecific feature sharply dropped over PMD, even within our very short intervals.…”

Section: Discussionmentioning

confidence: 95%

“…The only attempter in this subset did not contribute an extreme value of P2RX7 + nuclei. It has been proven that the heterogeneity of the P2RX7 gene was strongly linked to cognitive deficits, a key factor in the suicide processes 35,36 . Therefore, the distinctive presence of P2RX7 + nuclei in the DG may provide a pointcut for deciphering the suicide-specific cognitive inflexibility.…”

Section: Discussionmentioning

confidence: 99%

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

Zhang

Verwer

Heerikhuize

et al. 2022

Preprint

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Imbalanced purine metabolism is a key neurological basis for suicide and mood disorders (MD), wherein purinergic receptors in stress-sensitive cerebral regions are thought to be differentially activated. A hippocampal network that links the hypothalamus and prefrontal cortex implements an affective sensation of stress. We discovered that the hippocampus encoded fatal suicidal ideations in the dentate gyrus (DG) by a considerable amount of the granule cell nuclei with P2X purinoceptor 7 (P2RX7) expression, irrespective of the underlying MD. Compared to controls, patients with MD showed microglial dyshomeostasis throughout the hippocampal formation. Strikingly, P2Y purinoceptor 12 (P2RY12)-expressing microglia with segmented processes were remarkably present in the superficial layers of the medial entorhinal cortex (mEnt) in individuals with fatal suicidality. In the hypothalamic stress-sensitive nuclei, P2RY12+ microglia were more expressed in the supraoptic nucleus in MD and even higher when fatal suicidality was present. In the prefrontal cortex, P2RX7 transcripts sharply dropped in suicidal individuals, possibly removing the prefrontal inhibition of the hippocampus and hypothalamus. Confounder analysis showed that the suicide-specific molecular features faded when the postmortem delay was prolonged. Our findings imply that fatal suicidality presents with unique neuropathological alterations. The DG and mEnt are two crucial areas for deciphering the suicidal consequences. By including brain samples from legal euthanasia donors, suicide-specific biosignatures can be maximally retained. Decoding the bioactive framework through key genes, brain regions and neurological processes involved in suicide neuropathology may provide novel therapeutic strategies for suicidal individuals who are beyond the reach of mental health care.

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“…Cognitive deficits of BD patients were widely reported in a range of domains, including attention, verbal learning, and mental flexibility [ 21 ]. Zhang et al reviewed that cognitive dysfunction is one important parameter implicated in suicidality [ 22 ], but Gilbert et al did not find the association between cognition and suicide attempt [ 23 ]. Xu et al reported that there was a difference in domains of cognition between male and female BD patients [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Association of childhood trauma, social support, cognition, and suicidality in females with bipolar disorder

Yang,

Li,

et al. 2024

BMC Psychiatry

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Background Bipolar disorder (BD) is a severe mental disorder with heavy disease burden. Females with BD are special populations who suffer a lot from childhood trauma, social support, cognitive deficits, and suicidality. In this study, the relationship among childhood trauma, social support, and clinical symptoms of BD was investigated and the risk factors for suicidality were explored in female patients with BD. Methods This study included 57 drug-naive female BD patients, 64 female BD patients with long-term medication, and 50 age-matched female healthy controls. Childhood trauma, social support, clinical symptoms, cognition, and suicidality (suicide ideation, suicide plan, suicide attempt, suicide frequency) were measured with scales. Results Compared with healthy controls, females with BD showed higher levels of childhood trauma and suicidality, and lower levels of social support and cognitive deficits. In the drug-naïve BD group, social support mediated the relationship between childhood trauma and insomnia symptoms (indirect effect: ab = 0.025). In the BD with long-term medication group, mania symptom was associated with suicide plan (OR = 1.127, p = 0.030), childhood trauma was associated with suicide attempt (OR = 1.088, p = 0.018), and years of education (OR = 0.773, p = 0.028), childhood trauma (OR = 1.059, p = 0.009), and delayed memory (OR= 1.091, p= 0.016) was associated with suicide frequency (OR = 1.091, p = 0.016). Conclusions This study provides initial evidence that social support partially explains the relationship between childhood trauma and clinical symptoms in females with BD. Additionally, mania symptoms, childhood trauma, and delayed memory were risk factors for suicidality. Interventions providing social support and improving cognitive function may be beneficial for females with BD who are exposed to childhood trauma and with high suicide risk.

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Hippocampal neuropathology in suicide: Gaps in our knowledge and opportunities for a breakthrough

Cited by 14 publications

References 187 publications

Paradoxical Anxiety Level Reduction in Animal Chronic Stress: A Unique Role of Hippocampus Neurobiology

Paradoxical Anxiety Level Reduction in Animal Chronic Stress: A Unique Role of Hippocampus Neurobiology

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

Association of childhood trauma, social support, cognition, and suicidality in females with bipolar disorder

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