The Potential Role of Metalloproteinases in Neurogenesis in the Gerbil Hippocampus Following Global Forebrain Ischemia

BACKGROUND: Matrix metalloproteinases (MMPs) have recently been considered to be involved in the neurogenic response of adult neural stem/progenitor cells. However, there is a lack of information showing direct association between the activation of MMPs and the development of neuronal progenitor cells involving proliferation and/or further differentiation in vulnerable (Cornus Ammoni-CA1) and resistant (dentate gyrus-DG) to ischemic injury areas of the brain hippocampus. PRINCIPAL FINDINGS: We showed that dynamics of MMPs activation in the dentate gyrus correlated closely with the rate of proliferation and differentiation of progenitor cells into mature neurons. In contrast, in the damaged CA1 pyramidal cells layer, despite the fact that some proliferating cells exhibited antigen specific characteristic of newborn neuronal cells, these did not attain maturity. This coincides with the low, near control-level, activity of MMPs. The above results are supported by our in vitro study showing that MMP inhibitors interfered with both the proliferation and differentiation of the human neural stem cell line derived from umbilical cord blood (HUCB-NSCs) toward the neuronal lineage. CONCLUSION: Taken together, the spatial and temporal profiles of MMPs activity suggest that these proteinases could be an important component in neurogenesis-associated processes in post-ischemic brain hippocampus

Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates

Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants

Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

Foliation deficits of cerebellum-selective Pax6 conditional mutants

Transcription factor Pax6 is a key regulator of progenitor cells in the mammalian telencephalon and eye, and it is also expressed during the development of the cerebellum. Studies using Pax6 knock out (KO) mice have revealed its critical role for the prenatal generation and migration of cerebellar granule cell progenitors as well as for the establishment of progenitor domains in the hindbrain. However, the perinatal mortality of these mice hindered the study of the role of Pax6 during postnatal cerebellar development, which is the period when most granule neurons are born in mammals.Here we used the Cre/loxP system to conditionally inactivate Pax6 in the cerebellum of developing and adult mice, which allowed us to investigate viable mutants. To this goal, we generated a novel transgenic mouse Cre line, in which the Cre recombinase is placed behind a Pax6 regulatory sequence. Crossing this Cre line with reporter lines (ZAP and ROSA26-lacZ) demonstrated the strongest activity in the cerebellum, especially in the anterior lobes, while weaker expression was detected in telencephalon, eye and pancreas. We then crossed the Pax6Cre line with the Pax6flox/flox transgenic mice carrying loxP sequences allowing inactivation of Pax6 function upon Cre expression. The double-mutant mice were viable and thus allowed us to investigate the effects of Pax6 loss-of-function (LOF) for postnatal cerebellar development. The mutants exhibited significantly diminished cerebellum with abnormal foliation, especially in the anterior lobes, coincident with the strongest Cre activity. The mice had ectopic clusters of Purkinje cells in the white matter surrounded by granule cells and GABAergic neurons. Thus, the Pax6Cre::Pax6flox/flox transgenic mice appear a useful tool to study the consequences of postnatal LOF of Pax6 in the cerebellum

Deficiency of Parvalbumin-positive cortical interneurons in Zbtb20 knock out mice

The developing mammalian forebrain is divided into two major regions: the pallium and the subpallium. The pallium is the site of generation of all glutamatergic pyramidal neurons while the subpalium, including the Medial ganglionic eminence (MGE), Lateral ganglionic eminence (LGE) and Caudal ganglionic eminence (CGE), gives rise to all cortical and striatal interneurons (INs), which are mostly GABAergic. In particular, MGE and CGE are the site of origin of nearly all cortical INs. The genesis of the large variety of INs is controlled by an array of genes expressed in specific locations during defined time windows. ZBTB20, a zinc finger/BTB domain-containing 20 gene, is a transcriptional repressor known for its critical role during hippocampal development. The expression of Zbtb20 in the ganglionic eminences warranted examination of its role for cortical INs. To address this issue, we took advantage of the Zbtb20 knock out (KO) mice generated by us. We studied the expression of Zbtb20 in MGE and CGE progenitors and found that nearly all of the Nkx2.1-positive precursors, which generate cortical Parvalbumin (PV)-positive INs, expressed Zbtb20. The cortices of the homozygous Zbtb20 KO mice exhibited a nearly complete absence of PV+ INs, while the heterozygous mutants showed only a slight decrease of these cells. These data suggest a dose-dependent effect of Zbtb20 for proper generation of PV+ cortical INs, the largest inhibitory neuronal fraction in the cortex

Subpopulations of human fetal cortical microglia express markers IBA1 and HAM56

Microglia are resident mononuclear phagocytes of the central nervous system (CNS), which regulate postnatal normal brain function. Under physiological conditions they actively survey their cell-specific territory with fine elongated processes, while in response to pathological stimuli they can transform into an activated amoeboid for. Microglia act as sentinels, detecting the slightest signs of tissue invasion or damage, capable of phagocytosing both neuronal debris and foreign agents. Recently, microglial functions were extended to processes such as embryonic and adult neurogenesis as well as postnatal synapse formation.We evaluated the density and distribution of microglial cells marked by ionized calcium-binding adapter molecule 1 (IBA1), marker that labels nearly all microglial cells, in the dorsal and ventral telencephalon of human abortion cases aged 17-21 gestational weeks (GW). In particular, we studied whether there would be differences in the density of IBA1-labeled microglia in different germinative layers of the developing pallium. We found higher density in the subventricular zone (SVZ) as compared to the ventricular (VZ) or intermediate (IZ) zones of the dorsal pallium. The percentage of mitotically active microglia was highest in the outer subventricular (oSVZ) and marginal zonez (MZ).We assessed the relationship in expression between the microglial-specific marker Iba1 and Ham56, which labels blood-borne tissue-specific macrophages in the ventricular and inner subventricular zones in the developing human forebrain. Double labeling revealed a distinct subset of cells, positive for both markers, thus demonstrating the existence of IBA1+/HAM56+ and IBA1+/HAM56- subpopulations of microglia. Overall, our results show differential distribution of microglia in the germinative zones of developing human telencephalon, which opens a possibility of a differential regulation of the progenitor cells located in these zones

Adipobiology of the brain: from brain diabetes to adipose Alzheimer‘s disease

Recent studies suggest that diabetes mellitus affects multiple cognitive functions including expression of amyloid precursor protein (APP), amyloid-β (Aβ) peptide and hyperphosphorylated Tau - molecular signatures of Alzheimer`s disease (AD). Further, the administration of streptozotocin (STZ), a well known experimental model for diabetes, induces brain insulin resistance and cognitive alterations resembling those in AD patients. Thus the STZ treatment became a new experimental tool in studying AD, which is increasingly evaluated as type 3 diabetes. Accordingly, the concept of brain diabetes was introduced. We have reported that STZ-induced diabetes is associated with changes in nerve growth factor (NGF) levels in both pancreas and brain (Arch Ital Biol 2007; 145:87-97). Intriguingly, data of an extraneuronal production of both APP and Aβ peptides including in the adipose tissue were reported. In the last 20 years, adipose tissue and its endocrine secretory proteins (adipokines) take center stage in studying cardiometabolic (including diabetes) and neurodegenerative (including AD) diseases, both associated with adipose-derived neurometabotrophic factors (e.g. NGF, BDNF, leptin, adiponectin, betatrophin, neudesin, progranulin, irisin) (World J Pharmacol 2013; 2: 92-99). Altogether, our hypothesis of adipose tissue as a third brain (Obesity Metab 2009; 5: 94-96; Cell Biol Int 2010; 34:1051-1053), herein referred to as adipose AD, may sound more plausible at present. However, the major questions which remain to be answered are: (i) may AD pathology spread from the adipose tissue to the brain, and (ii) may AD be considered a neurometabolic disease