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Addiction Biology May 2021Alcohol abuse and dependence are world-wide health problems. Most research on alcohol use focuses on the consequences of moderate to high levels of alcohol. However,...
Alcohol abuse and dependence are world-wide health problems. Most research on alcohol use focuses on the consequences of moderate to high levels of alcohol. However, even at low concentrations, alcohol is capable of producing effects in the brain that can ultimately affect behavior. The current studies seek to understand the effects of low-dose alcohol (blood alcohol levels of ≤10mM). To do so, these experiments utilize a combination of behavioral and molecular techniques to (1) assess the ability of the interoceptive effects of a low dose of alcohol to gain control over goal-tracking behavior in a Pavlovian discrimination task, (2) determine brain regional differences in cellular activity via expression of immediate early genes (IEGs), and (3) assess the role of the dentate gyrus in modulating sensitivity to the interoceptive effects of a low dose of alcohol. Here, we show that intragastric administration of a dose of 0.8 g/kg alcohol produces blood alcohol levels ≤10mM in both male and female Long-Evans rats and can readily be trained as a Pavlovian interoceptive drug cue. In rats trained on this procedure, this dose of alcohol also modulates expression of the IEGs c-Fos and Arc in brain regions known to modulate expression of alcohol interoceptive effects. Finally, pharmacological inactivation of the dentate gyrus with GABA agonists baclofen and muscimol disrupted the ability of a low dose of alcohol to serve as an interoceptive cue. Together, these findings demonstrate behavioral and molecular consequences of low-dose alcohol.
Topics: Animals; Baclofen; Behavior, Animal; Dentate Gyrus; Discrimination Learning; Ethanol; Female; Male; Muscimol; Rats; Rats, Long-Evans; Self Administration
PubMed: 33015936
DOI: 10.1111/adb.12965 -
Scientific Reports Oct 2023The hippocampal formation is one of the best studied brain regions for spatial and mnemonic representations. These representations have been reported to differ in their...
The hippocampal formation is one of the best studied brain regions for spatial and mnemonic representations. These representations have been reported to differ in their properties for individual hippocampal subregions. One approach that allows the detection of neuronal representations is immediate early gene imaging, which relies on the visualization of genomic responses of activated neuronal populations, so called engrams. This method permits the within-animal comparison of neuronal representations across different subregions. In this work, we have used compartmental analysis of temporal activity by fluorescence in-situ hybridisation (catFISH) of the immediate early gene zif268/erg1 to compare neuronal representations between subdivisions of the dentate gyrus and CA3 upon exploration of different contexts. Our findings give an account of subregion-specific ensemble sizes. We confirm previous results regarding disambiguation abilities in dentate gyrus and CA3 but in addition report novel findings: Although ensemble sizes in the lower blade of the dentate gyrus are significantly smaller than in the upper blade both blades are responsive to environmental change. Beyond this, we show significant differences in the representation of familiar and novel environments along the longitudinal axis of dorsal CA3 and most interestingly between CA3 regions of both hemispheres.
Topics: Animals; Dentate Gyrus; Hippocampus; Neurons; Memory; Brain
PubMed: 37891194
DOI: 10.1038/s41598-023-45304-y -
Biological Psychiatry Sep 2020Parvalbumin (PV)-expressing interneurons are important for cognitive and emotional behaviors. These neurons express high levels of p11, a protein associated with...
BACKGROUND
Parvalbumin (PV)-expressing interneurons are important for cognitive and emotional behaviors. These neurons express high levels of p11, a protein associated with depression and action of antidepressants.
METHODS
We characterized the behavioral response to subthreshold stress in mice with conditional deletion of p11 in PV cells. Using chemogenetics, viral-mediated gene delivery, and a specific ion channel agonist, we studied the role of dentate gyrus PV cells in regulating anxiety-like behavior and resilience to stress. We used electrophysiology, imaging, and biochemical studies in mice and cells to elucidate the function and mechanism of p11 in dentate gyrus PV cells.
RESULTS
p11 regulates the subcellular localization and cellular level of the potassium channel Kv3.1 in cells. Deletion of p11 from PV cells resulted in reduced hippocampal level of Kv3.1, attenuated capacity of high-frequency firing in dentate gyrus PV cells, and altered short-term plasticity at synapses on granule cells, as well as anxiety-like behavior and a pattern separation deficit. Chemogenetic inhibition or deletion of p11 in these cells induced vulnerability to depressive behavior, whereas upregulation of Kv3.1 in dentate gyrus PV cells or acute activation of Kv3.1 using a specific agonist induced resilience to depression.
CONCLUSIONS
The activity of dentate gyrus PV cells plays a major role in the behavioral response to novelty and stress. Activation of the Kv3.1 channel in dentate gyrus PV cells may represent a target for the development of cell-type specific, fast-acting antidepressants.
Topics: Animals; Dentate Gyrus; Depression; Interneurons; Mice; Neurons; Parvalbumins
PubMed: 32331822
DOI: 10.1016/j.biopsych.2020.02.1179 -
Proceedings of the National Academy of... Apr 2022Genetic studies of hippocampal granule neuron development have been used to elucidate cellular functions of Pten and Fmr1. While mutations in each gene cause...
Genetic studies of hippocampal granule neuron development have been used to elucidate cellular functions of Pten and Fmr1. While mutations in each gene cause neurodevelopmental disorders such as autism and fragile X syndrome, how Pten and Fmr1 function alone or together during normal development is not known. Moreover, Pten mRNA is bound by the fragile X mental retardation protein (FMRP) RNA binding protein, but how this physical interaction impinges on phosphatase and tensin homolog protein (PTEN) expression is not known. To understand the interaction of PTEN and FMRP, we investigated the dentate gyrus granule neuron development in Pten and Fmr1 knockout (KO) mice. Interestingly, heterozygosity of Pten restored Fmr1 KO cellular phenotypes, including dendritic arborization, and spine density, while PTEN protein expression was significantly increased in Fmr1 KO animals. However, complete deletion of both Pten and Fmr1 resulted in a dramatic increase in dendritic length, spine density, and spine length. In addition, overexpression of PTEN in Fmr1 KO Pten heterozygous background reduced dendritic length, arborization, spine density, and spine length including pS6 levels. Our findings suggest that PTEN levels are negatively regulated by FMRP, and some Fmr1 KO phenotypes are caused by dysregulation of PTEN protein. These observations provide evidence for the genetic interaction of PTEN and FMRP and a possible mechanistic basis for the pathogenesis of Fmr1-related fragile X neurodevelopmental disorders.
Topics: Animals; Dentate Gyrus; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Heterozygote; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurogenesis; Neurons; PTEN Phosphohydrolase
PubMed: 35394871
DOI: 10.1073/pnas.2109448119 -
Hippocampus Apr 2022Information processing in cortical circuits, including the hippocampus, relies on the dynamic control of neuronal activity by GABAergic interneurons (INs). INs form a...
Information processing in cortical circuits, including the hippocampus, relies on the dynamic control of neuronal activity by GABAergic interneurons (INs). INs form a heterogenous population with defined types displaying distinct morphological, molecular, and physiological characteristics. In the major input region of the hippocampus, the dentate gyrus (DG), a number of IN types have been described which provide synaptic inhibition to distinct compartments of excitatory principal cells (PrCs) and other INs. In this study, we perform an unbiased classification of GABAergic INs in the DG by combining in vitro whole-cell patch-clamp recordings, intracellular labeling, morphological analysis, and unsupervised cluster analysis to better define IN type diversity in this region. This analysis reveals that DG INs divide into at least 13 distinct morpho-physiological types which reflect the complexity of the local IN network and serve as a basis for further network analyses.
Topics: Animals; Dentate Gyrus; Hippocampus; Interneurons; Neurons; Patch-Clamp Techniques; Rats
PubMed: 35171512
DOI: 10.1002/hipo.23408 -
The Journal of Toxicological Sciences 2020Bisphenol A (BPA), an endocrine disruptor with estrogenic effects, is widely used as a raw material for manufacturing polycarbonate plastic and epoxy resins. Prenatal...
Bisphenol A (BPA), an endocrine disruptor with estrogenic effects, is widely used as a raw material for manufacturing polycarbonate plastic and epoxy resins. Prenatal and postnatal exposure to BPA affects brain morphogenesis. However, the effects of prenatal and postnatal BPA exposure on postnatal neurogenesis in mice are poorly understood. In this study, we developed a mouse model of prenatal and postnatal BPA exposure and analyzed its effects on hippocampal neurogenesis. The hippocampal dentate gyrus is vulnerable to chemical exposure, as neurogenesis continues in this region even after birth. Our results showed that in mice, prenatal and postnatal BPA exposure decreased the number of type-1, 2a, 2b, and 3 neural progenitor cells, as well as in granule cells, in the hippocampal dentate gyrus on postnatal days 16 and 70. The effect of prenatal and postnatal BPA exposure on neural progenitors were affected at all differentiation stages. In addition, prenatal and postnatal BPA exposure affects the maintenance of long-term memory on postnatal day 70. Our results suggest that neurodevelopmental toxicity due to prenatal and postnatal BPA exposure might affect postnatal morphogenesis and functional development of the hippocampal dentate gyrus.
Topics: Animals; Animals, Newborn; Benzhydryl Compounds; Cell Differentiation; Dentate Gyrus; Endocrine Disruptors; Female; Hippocampus; Male; Maternal Exposure; Maternal-Fetal Exchange; Mice; Models, Animal; Neural Stem Cells; Neurogenesis; Phenols; Pregnancy
PubMed: 33012732
DOI: 10.2131/jts.45.639 -
Hippocampus Nov 2021The dentate gyrus not only gates the flow of information into the hippocampus, it also integrates and processes this information. Mossy cells (MCs) are a major type of...
The dentate gyrus not only gates the flow of information into the hippocampus, it also integrates and processes this information. Mossy cells (MCs) are a major type of excitatory neuron strategically located in the hilus of the dentate gyrus where they can contribute to this processing through networks of synapses with inhibitory neurons and dentate granule cells. Some prior work has suggested that MCs can form excitatory synapses with other MCs, but the role of these synapses in the network activity of the dentate gyrus has received little attention. Here, we investigated synaptic inputs to MCs in mouse hippocampal slices using a genetically encoded hybrid voltage sensor (hVOS) targeted to MCs by Cre-lox technology. This enabled optical recording of voltage changes from multiple MCs simultaneously. Stimulating granule cells and CA3 pyramidal cells activated well-established inputs to MCs and elicited synaptic responses as expected. However, the weak blockade of MC responses to granule cell layer stimulation by DCG-IV raised the possibility of another source of excitation. To evaluate synapses between MCs as this source, single MCs were stimulated focally. Stimulation of one MC above its action potential threshold evoked depolarizing responses in neighboring MCs that depended on glutamate receptors. Short latency responses of MCs to other MCs did not depend on release from granule cell axons. However, granule cells did contribute to the longer latency responses of MCs to stimulation of other MCs. Thus, MCs transmit their activity to other MCs both through direct synaptic coupling and through polysynaptic coupling with dentate granule cells. MC-MC synapses can redistribute information entering the dentate gyrus and thus shape and modulate the electrical activity underlying hippocampal functions such as navigation and memory, as well as excessive excitation during seizures.
Topics: Animals; Dentate Gyrus; Hippocampus; Mice; Mossy Fibers, Hippocampal; Rats; Rats, Sprague-Dawley; Synapses
PubMed: 34478219
DOI: 10.1002/hipo.23386 -
Surgical and Radiologic Anatomy : SRA Feb 2020Recent scientific papers indicate the clinical significance of the dentate gyrus. However, a detailed knowledge of the anatomical variations of this structure in normal...
Recent scientific papers indicate the clinical significance of the dentate gyrus. However, a detailed knowledge of the anatomical variations of this structure in normal adult brain is still lacking. An understanding of the variable morphology of the dentate gyrus may be important for diagnostic neuroimaging. Thus, the purpose of this macroscopic cadaveric study was to describe the anatomical variations of the dentate gyrus. Forty formalin-fixed human cerebral hemispheres, obtained from bodies of donors without the history of neuropathological diseases, were included in the study. The dentate gyrus was classified as well-developed, when it protruded completely from under the fimbria of the hippocampus. The gyrus was classified as underdeveloped, when it was covered by the fimbria of the hippocampus (but clearly visible at the coronal section of the hippocampal formation), while the hypoplastic gyrus was not visible macroscopically under the fimbria of the hippocampus. The well-developed type was observed in 27 cases (67.5%). The thickness of well-developed type of the dentate gyrus, measured between the fimbriodentate sulcus and hippocampal sulcus, varied from 2.74 to 5.21 mm (mean = 3.67 mm, median = 5.54 mm, SD 0.65 mm). In the next nine cases (22.5%), the dentate gyrus was underdeveloped. The thickness of underdeveloped type of the dentate gyrus varied from 1.75 to 2.37 mm (mean = 2.02 mm, median = 2.16 mm, SD 0.33 mm). In the remaining four cases (10%), the dentate gyrus was hypoplastic and could not be distinguished macroscopically. In all injected hemispheres, arterial supply of the dentate gyrus was provided by the branches of the posterior cerebral artery. Awareness of normal variations of the dentate gyrus may allow for better correlation of anatomical knowledge with radiological data and for use this knowledge to describe abnormal conditions.
Topics: Adult; Anatomic Variation; Cadaver; Dentate Gyrus; Humans
PubMed: 31372742
DOI: 10.1007/s00276-019-02298-5 -
Molecular Brain Nov 2022The development, maturation, and plasticity of neural circuits are strongly influenced by experience and the interaction of an individual with their environment can have...
The development, maturation, and plasticity of neural circuits are strongly influenced by experience and the interaction of an individual with their environment can have a long-lasting effect on cognitive function. Using an enriched environment (EE) paradigm, we have recently demonstrated that enhancing social, physical, and sensory activity during the pre-weaning time in mice led to an increase of inhibitory and excitatory synapses in the dentate gyrus (DG) of the hippocampus. The structural plasticity induced by experience may affect information processing in the circuit. The DG performs pattern separation, a computation that enables the encoding of very similar and overlapping inputs into dissimilar outputs. In the presented study, we have tested the hypothesis that an EE in juvenile mice will affect DG's functions that are relevant for pattern separation: the decorrelation of the inputs from the entorhinal cortex (EC) and the recruitment of the principal excitatory granule cell (GC) during behavior. First, using a novel slice electrophysiology protocol, we found that the transformation of the incoming signal from the EC afferents by individual GC is moderately affected by EE. We further show that EE does not affect behaviorally induced recruitment of principal excitatory GC. Lastly, using the novel object recognition task, a hippocampus-dependent memory test, we show that the ontogeny of this discrimination task was similar among the EE mice and the controls. Taken together, our work demonstrates that pre-weaning enrichment moderately affects DG function.
Topics: Animals; Mice; Dentate Gyrus; Hippocampus; Entorhinal Cortex; Neurons; Synapses
PubMed: 36411441
DOI: 10.1186/s13041-022-00980-1 -
Cerebral Cortex (New York, N.Y. : 1991) May 2023Prematurely born infants are deprived of maternal hormones and cared for in the stressful environment of Neonatal Intensive Care Units (NICUs). They suffer from...
Prematurely born infants are deprived of maternal hormones and cared for in the stressful environment of Neonatal Intensive Care Units (NICUs). They suffer from long-lasting deficits in learning and memory. Here, we show that prematurity and associated neonatal stress disrupt dentate gyrus (DG) development and induce long-term cognitive deficits and that these effects are mediated by insulin growth factor-1 (IGF1). Nonmaternal care of premature rabbits increased the number of granule cells and interneurons and reduced neurogenesis, suggesting accelerated premature maturation of DG. However, the density of glutamatergic synapses, mature dendritic spines, and synaptic transmission were reduced in preterm kits compared with full-term controls, indicating that premature synaptic maturation was abnormal. These findings were consistent with cognitive deficits observed in premature rabbits and appeared to be driven by transcriptomic changes in the granule cells. Preterm kits displayed reduced weight, elevated serum cortisol and growth hormone, and higher IGF1 expression in the liver and DG relative to full-term controls. Importantly, blocking IGF-1 receptor in premature kits restored cognitive deficits, increased the density of glutamatergic puncta, and rescued NR2B and PSD95 levels in the DG. Hence, IGF1 inhibition alleviates prematurity-induced cognitive dysfunction and synaptic changes in the DG through modulation of NR2B and PSD95. The study identifies a novel strategy to potentially rescue DG maldevelopment and cognitive dysfunction in premature infants under stress in NICUs.
Topics: Animals; Rabbits; Dentate Gyrus; Cognitive Dysfunction; Transcription Factors; Cognition; Intercellular Signaling Peptides and Proteins; Insulins
PubMed: 36646459
DOI: 10.1093/cercor/bhac516