The effects of living in an outdoor enclosure on hippocampal plasticity and anxiety‐like behavior in response to nematode infection

The hippocampus of rodents undergoes structural remodeling throughout adulthood, including the addition of new neurons. Adult neurogenesis is sensitive to environmental enrichment and stress. Microglia, the brain's resident immune cells, are involved in adult neurogenesis by engulfing dying new neurons. While previous studies using laboratory environmental enrichment have investigated alterations in brain structure and function, they do not provide an adequate reflection of living in the wild, in which stress and environmental instability are common. Here, we compared mice living in standard laboratory settings to mice living in outdoor enclosures to assess the complex interactions among environment, gut infection, and hippocampal plasticity. We infected mice with parasitic worms and studied their effects on adult neurogenesis, microglia, and functions associated with the hippocampus, including cognition and anxiety regulation. We found an increase in immature neuron numbers of mice living in outdoor enclosures regardless of infection. While outdoor living prevented increases in microglial reactivity induced by infection in both the dorsal and ventral hippocampus, outdoor mice with infection had fewer microglia and microglial processes in the ventral hippocampus. We observed no differences in cognitive performance on the hippocampus‐dependent object location task between infected and uninfected mice living in either setting. However, we found that infection caused an increase in anxiety‐like behavior in the open field test but only in outdoor mice. These findings suggest that living conditions, as well as gut infection, interact to produce complex effects on brain structure and function.     

Axonal projection‐specific differences in somatodendritic α2 autoreceptor function in locus coeruleus neurons

The locus coeruleus (LC) contains the majority of central noradrenergic neurons sending wide projections throughout the entire CNS. The LC is considered to be essential for multiple key brain functions including arousal, attention and adaptive stress responses as well as higher cognitive functions and memory. Electrophysiological studies of LC neurons have identified several characteristic functional features such as low‐frequency pacemaker activity with broad action potentials, transient high‐frequency burst discharges in response to salient stimuli and an apparently homogeneous inhibition of firing by activation of somatodendritic α2 autoreceptors (α2AR). While stress‐mediated plasticity of the α2AR response has been described, it is currently unclear whether different LC neurons projecting to distinct axonal targets display differences in α2AR function. Using fluorescent beads‐mediated retrograde tracing in adult C57Bl6/N mice, we compared the anatomical distributions and functional in vitro properties of identified LC neurons projecting either to medial prefrontal cortex, hippocampus or cerebellum. The functional in vitro analysis of LC neurons confirmed their mostly uniform functional properties regarding action potential generation and pacemaker firing. However, we identified significant differences in tonic and evoked α2AR‐mediated responses. While hippocampal‐projecting LC neurons were partially inhibited by endogenous levels of norepinephrine and almost completely silenced by application of saturating concentrations of the α2 agonist clonidine, prefrontal‐projecting LC neurons were not affected by endogenous levels of norepinephrine and only partially inhibited by saturating concentrations of clonidine. Thus, we identified a limited α2AR control of electrical activity for prefrontal‐projecting LC neurons indicative of functional heterogeneity in the LC‐noradrenergic system.     

Neurogenesis in the adult hippocampus: history,regulation, and prospective roles

Background: The hippocampus is one of the sites in the mammalian brain that is capable of continuously generating controversy. Adult neurogenesis is a remarkable process, and yet an intensely debatable topic in contemporary neuroscience due to its distinctiveness and conceivable impact on neural activity. The belief that neurogenesis continues through adulthood has provoked remarkable efforts to describe how newborn neurons differentiate and incorporate into the adult brain. It has also encouraged studies that investigate the consequences of inadequate neurogenesis in neuropsychiatric and neurodegenerative diseases and explore the potential role of neural progenitor cells in brain repair. The adult nervous system is not static; it is subjected to morphological and physiological alterations at various levels. This plastic mechanism guarantees that the behavioral regulation of the adult nervous system is adaptable in response to varying environmental stimuli. Three regions of the adult brain, the olfactory bulb, the hypothalamus, and the hippocampal dentate gyrus, contain new-born neurons that exhibit an essential role in the natural functional circuitry of the adult brain. Purpose/Aim: This article explores current advancements in adult hippocampal neurogenesis by presenting its history and evolution and studying its association with neural plasticity. The article also discusses the prospective roles of adult hippocampal neurogenesis and describes the intracellular, extracellular, pathological, and environmental factors involved in its regulation. Abbreviations AHN Adult hippocampal neurogenesis

AKT Protein kinase B

BMP Bone Morphogenic Protein

BrdU Bromodeoxyuridine

CNS Central nervous system

DG Dentate gyrus

DISC1 Disrupted-in-schizophrenia 1

FGF-2 Fibroblast Growth Factor 2

GABA Gamma-aminobutyric acid

Mbd1 Methyl-CpG-binding domain protein 1

Mecp2 Methyl-CpG-binding protein 2

mTOR Mammalian target of rapamycin

NSCs Neural stem cells

OB Olfactory bulb; P21: cyclin-dependent kinase inhibitor 1

RBPj Recombination Signal Binding protein for Immunoglobulin Kappa J Region

RMS Rostral migratory Stream

SGZ Subgranular zone

Shh Sonic hedgehog

SOX2 SRY (sex determining region Y)-box 2

SVZ Subventricular zone

Wnt3 Wingless-type mouse mammary tumor virus

     

Distinct differences in rates of oxygen consumption and ATP synthesis of regionally isolated non-synaptic mouse brain mitochondria

Brain mitochondrial dysfunction has been implicated in several neurodegenerative diseases. The distribution and efficiency of mitochondria display large heterogeneity throughout the regions of the brain. This may imply that the selective regional susceptibility of neurodegenerative diseases could be mediated through inherent differences in regional mitochondrial function. To investigate regional cerebral mitochondrial energetics, the rates of oxygen consumption and adenosine-5′-triphosphate (ATP) synthesis were assessed in isolated non-synaptic mitochondria of the cerebral cortex, hippocampus, and striatum of the male mouse brain. Oxygen consumption rates were assessed using a Seahorse XFe96 analyzer and ATP synthesis rates were determined by an online luciferin-luciferase coupled luminescence assay. Complex I- and complex II-driven respiration and ATP synthesis, were investigated by applying pyruvate in combination with malate, or succinate, as respiratory substrates, respectively. Hippocampal mitochondria exhibited the lowest basal and adenosine-5′-diphosphate (ADP)-stimulated rate of oxygen consumption when provided pyruvate and malate. However, hippocampal mitochondria also exhibited an increased proton leak and an elevated relative rate of oxygen consumption in response to the uncoupler carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), showing a large capacity for uncoupled respiration in the presence of pyruvate. When the complex II-linked substrate succinate was provided, striatal mitochondria exhibited the highest respiration and ATP synthesis rate, whereas hippocampal mitochondria had the lowest. However, the mitochondrial efficiency, determined as ATP produced/O₂ consumed, was similar between the three regions. This study reveals inherent differences in regional mitochondrial energetics and may serve as a tool for further investigations of regional mitochondrial function in relation to neurodegenerative diseases.     

Spatial object recognition memory formation under acute stress

Stress is known to have a critical impact on memory processes. In the present work, we focus on the effects of an acute stress event closely associated to an unrelated learning task. Here, we show that acute stress (elevated platform [EP] session) experienced 1 hr after a weak spatial object recognition (SOR) training, which only induces a short‐term memory (STM), promoted the formation of SOR‐long term memory (SOR‐LTM) in rats. The effect induced by stress was dependent on the activation of glucocorticoid‐ and mineralocorticoid‐receptors, brain‐derived neurotrophic factor (BDNF) and protein synthesis in the dorsal hippocampus. In contrast, EP after a strong SOR impaired SOR‐LTM probably by interfering with the use of necessary resources. Moreover, we show that the EP session before training induced anterograde interference, which it was not reversed by a subsequent exposure to an open field. Our findings provide novel insights into the impact of stress on LTM formation in rodents and they are discussed under the behavioral analogue of the synaptic tagging and capture hypothesis.     

Absence of an early hippocampal encoding signal after medial temporal lesions: No consequence for the spacing effect

Immediately repeated meaningful pictures in a continuous recognition task induce a positive frontal potential at about 200–300 ms, which appears to emanate from the medial temporal lobe (MTL) centered on the hippocampus, as concluded from inverse solutions, coherence measurements, and depth electrode recordings in humans. In this study, we tested patients with unilateral MTL lesions due to stroke to verify the provenance of this signal and its association with the spacing effect (SE)—the improved learning of material encountered in spaced rather than massed presentation. We found that unilateral left or right MTL lesions abolished the early frontal MTL‐mediated signal but not the spacing effect. We conclude that the SE does not depend on MTL integrity. We suggest that the early frontal signal at 200–300 ms after immediate picture repetition may serve as a direct biomarker of MTL integrity that may be useful in the early stages of diseases like Alzheimer's.