Albrecht A, Müller I, Weiglein A, Pollali E, Çalışkan G, Stork O. (2022). Choosing memory retrieval strategies: A critical role for inhibition in the dentate gyrus. Neurobiology of Stress 20:100474. doi: 10.1016/j.ynstr.2022.100474. PMID: 35958670; PMCID: PMC9357949.
Remembering the location of food is essential for survival. Rodents and humans employ mainly hippocampus-dependent spatial strategies, but when being stressed they shift to striatum-mediated stimulus-based strategies. To investigate underlying brain circuits, we tested mice with a heightened stress susceptibility due to a lack of the GABA-synthetizing enzyme GAD65 (GAD65-/- mice) in a dual solution task. Here, GAD65-/- mice preferred to locate a food reward in an open field via a proximal cue, while their wildtype littermates preferred a spatial strategy. The analysis of cFos co-activation across brain regions and of stress-induced mRNA expression changes of GAD65 pointed towards the hippocampal dorsal dentate gyrus (dDG) as a central structure for mediating stress effects on strategy choices via GAD65. Reducing the GAD65 expression locally in the dDG by a shRNA mediated knock down was sufficient to replicate the phenotype of the global GAD65 knock out and to increase dDG excitability. Using DREADD vectors to specifically interfere with dDG circuit activity during dual solution retrieval but not learning confirmed that the dDG modulates strategy choices and that a balanced excitability of this structure is necessary to establish spatial strategy preference. These data highlight the dDG as a critical hub for choosing between spatial and non-spatial foraging strategies.
Keywords: Cognitive flexibility; Dentate gyrus; GAD65; Inhibition; Spatial learning; Stimulus-based learning.
Albrecht A, Segal M, Stork, O. (2022). Allostatic gene regulation of inhibitory synaptic factors in the rat ventral hippocampus in a juvenile/adult stress model of psychopathology. European journal of neuroscience 55 (9/10): 2142-2153. http://dx.doi.org/10.1111/ejn.15091 10.25673/85178
Early life stress is an important vulnerability factor for the development of anxiety disorders, depression and late-onset cognitive decline. Recently, we demonstrated that juvenile stress (JS) lastingly enhanced long-term potentiation via reduction of steady-state glutamine synthetase mRNA expression and the associated dysregulation of the astrocytic glutamate-glutamine cycle in the rat ventral CA1. We now investigated the regulation of steady-state mRNA expression of neuronal gene products that determine GABAergic and glutamatergic neurotransmission in layers of the ventral and dorsal CA1 after JS. We further studied their interaction with stress in young adult age (AS) to address their putative role in psychopathology development. Strikingly, mRNA levels of the glutamic acid decarboxylase (GAD) isoforms GAD65 and of the GABA-A receptor α2 (Gabra2) were increased after single JS or AS, but not after combined JS/AS stress experience. In fact, JS/AS resulted in layer-specific reduction of Gabra2 and also of Gabra1 mRNA levels in the ventral CA1. Furthermore, GAD65 and Gabra2 mRNAs were correlated with glutamatergic AMPA and NMDA receptor subunit mRNAs after single JS and AS, but not after combined JS/AS. Together, these data indicate a loss of allostatic regulation of steady-state mRNA levels of key GABAergic components that may result in a dysregulation of excitation/ inhibition balance in the ventral CA1 upon dual stress exposure. Finally, individual differences in local glucocorticoid receptor mRNA expression may contribute to this regulation.
Keywords: GAD65; Gabra2; inhibition; juvenile stress; ventral CA1.
Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function.Madencioglu DA, Çalışkan G, Yuanxiang P, Rehberg K, Demiray YE, Kul E, Engler A, Hayani H, Bergado-Acosta JR, Kummer A, Müller I, Song I, Dityatev A, Kähne T, Kreutz MR, Stork O.iScience. 2021 Jul 19;24(8):102868. doi: 10.1016/j.isci.2021.102868
Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The NDR2 gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions. Our analysis reveals reduced terminal fields and synaptic transmission of hippocampal mossy fibers, altered hippocampal network activity, and deficits in mossy fiber-dependent behaviors. Reduced doublecortin expression and protein interactome analysis indicate that transgenic Ndr2 disturbs the maturation of granule cells in the dentate gyrus. Together, our data suggest that increased expression of Ndr2 may critically contribute to the development of intellectual disabilities upon gene amplification.
Keywords: genetics; neuroscience; sensory neuroscience.
The new research unit 5228 “Syntophagy”, a collaboration of researchers in Magdeburg, Berlin, Bremen and Haifa has been awarded funding by the German Research Foundation. The consortium lead by Dr. Michael Kreutz of the Leibniz Institute for Neurobiology in Magdeburg will examine the role of autophagy in synaptic functions. In our subproject, we join forces with Anne Albrecht at the Institute of Anatomy, OVGU, to study the control of stress related behaviour through autophagy in the hippocampus.
TRIPATHI K, DEMIRAY YE, KLICHE S, JING L, HAZRA S, HAZRA JD, RICHTER-LEVIN G, STORK O (2021) REDUCING GLUTAMIC ACID DECARBOXYLASE IN THE DORSAL DENTATE GYRUS ATTENUATES JUVENILE STRESS INDUCED EMOTIONAL AND COGNITIVE DEFICITS. NEUROBIOL STRESS 15:100350. DOI: 10.1016/J.YNSTR.2021.100350.
A high degree of regional, temporal and molecular specificity is evident in the regulation of GABAergic signaling in stress-responsive circuitry, hampering the use of systemic GABAergic modulators for the treatment of stress-related psychopathology. Here we investigated the effectiveness of local intervention with the GABA synthetic enzymes GAD65 and GAD67 in the dorsal dentate gyrus (dDG) vs ventral DG (vDG) to alleviate anxiety-like behavior and stress-induced symptoms in the rat. We induced shRNA-mediated knock down of either GAD65 or GAD67 with lentiviral vectors microinjected into the dDG or vDG of young adult male rats and examined anxiety behavior, learning and memory performance. Subsequently we tested whether reducing GAD65 expression in the dDG would also confer resilience against juvenile stress-induced behavioral and physiological symptoms in adulthood. While knock down of either isoform in the vDG increased anxiety levels in the open field and the elevated plus maze tests, the knock down of GAD65, but not GAD67, in the dDG conferred a significant reduction in anxiety levels. Strikingly, this manipulation also attenuated juvenile stress evoked anxiety behavior, cognitive and synaptic plasticity impairments. Local GABAergic circuitry in the DG plays an important and highly region-specific role in control of emotional behavior and stress responding. Reduction of GAD65 expression in the dDG appears to provide resilience to juvenile stress-induced emotional and cognitive deficits, opening a new direction towards addressing a significant risk factor for developing stress and trauma-related psychopathologies later in life.
Hippocampal gamma-band oscillopathy in a mouse model of Fragile X Syndrome
Evangelia Pollali, Jan-Oliver Hollnagel, Gürsel Çalışkan. doi: https://doi.org/10.1101/2021.04.24.441239
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability arising from the loss of fragile X mental retardation protein (FMRP), a protein that plays a central role in neuronal function and plasticity. FXS patients show sensory hypersensitivity, hyperarousal and hippocampus-dependent learning deficits that can be recapitulated in the FMR1 KO mice. Enhanced metabotropic glutamate receptor (mGluR) signaling and muscarinic acetylcholine receptor (mAChR) signaling in the FMR1 KO mouse are implicated as the primary causes of the disease pathogenesis. Furthermore, glutamatergic kainate receptor (KAR) function is reduced in the cortex of the FMR1 KO mice. Of note, activation of these signaling pathways leads to slow gamma-range oscillations in the hippocampus in vitro and abnormal gamma oscillations have been reported in FMR1 KO mice and patients with FXS. Thus, we hypothesized that aberrant activation of these receptors leads to the observed gamma oscillopathy. We recorded gamma oscillations induced by either cholinergic agonist carbachol (CCh), mGluR1/5 agonist Dihydroxyphenylglycine (DHPG) or ionotropic glutamatergic agonist KA from the hippocampal CA3 in WT and FMR1 KO mice in vitro. We show a specific increase in the power of DHPG and CCh-induced gamma oscillations and reduction in the synchronicity of gamma oscillations induced by KA. We further elucidate an aberrant spiking activity during CCh-induced and kainate-induced gamma oscillations which may underlie the altered gamma oscillation synchronization in the FMR1 KO mice. Last, we also noted a reduced incidence of spontaneously-occurring hippocampal sharp wave-ripple events. Our study provides further evidence for aberrant hippocampal rhythms in the FMR1 KO mice and identifies potential signaling pathways underlying gamma band oscillopathy in FXS.
To err is (not only) human: Mechanisms of post-error attentional regulation illuminated in mice. by Markus Ullsperger and Oliver Stork. https://doi.org/10.1016/j.neuron.2021.03.014
Errors yield unfavorable outcomes but also elicit adaptive mechanisms optimizing future behavior. Norman et al. demonstrate a previously unknown direct projection frommedial frontal performance-monitoring areas.
Magdalena Derbis, Emre Kul, Daria Niewiadomska , Michał Sekrecki, Agnieszka Piasecka, Katarzyna Taylor, Renate K. Hukema , Oliver Stork & Krzysztof Sobczak
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in the FMR1 5’UTR. The RNA containing expanded CGG repeats (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGGexp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.
We are looking for MD students who are enthusiastic about basic research to investigate age-related cognitive decline in mice using a novel touchscreen test system.
Our newest paper is online: Allostatic gene regulation of inhibitory synaptic factors in the rat ventral hippocampus in a juvenile/adult stress model of psychopathology by Anne Albrecht, Menahem Segal and Oliver Stork
Here we show the region-specific long-term regulation of GABA-related molecular factors in the hippocampus after a juvenile stress experience. Our data highlight the role of ventral hippocampus and mechanisms that control local excitation/inhibition balance in development in adaptive and maladaptive stress responding.
Early life stress is an important vulnerability factor for the development of anxiety disorders, depression and late-onset cognitive decline. Recently we demonstrated that juvenile stress (JS) lastingly enhanced long-term potentiation via reduction of steady-state glutamine synthetase mRNA expression and the associated dysregulation of the astrocytic glutamate-glutamine cycle in the rat ventral CA1. We now investigated the regulation of steady-state mRNA expression of neuronal gene products that determine GABAergic and glutamatergic neurotransmission in layers of the ventral and dorsal CA1 after JS. We further studied their interaction with stress in young adult age (AS) to address their putative role in psychopathology development. Strikingly, mRNA levels of the glutamic acid decarboxylase (GAD) isoforms GAD65 and of the GABA-A receptor a2 (Gabra2) were increased after single JS or AS, but not after combined JS/AS stress experience. In fact, JS/AS resulted in layer-specific reduction of Gabra2 and also of Gabra1 mRNA levels in the ventral CA1. Furthermore, GAD65 and Gabra2 mRNAs were correlated with glutamatergic AMPA and NMDA receptor subunit mRNAs after single JS and AS, but not after combined JS/AS. Together, these data indicate a loss of allostatic regulation of steady-state mRNA levels of key GABAergic components that may result in a dysregulation of excitation/ inhibition balance in the ventral CA1 upon dual stress exposure. Finally, individual differences in local glucocorticoid receptor mRNA expression may contribute to this regulation.