Umshweif review 2019


 * Impaired dendritic function in depression is accompanied by reduced expression of AMPA receptor subunits. Leads to reduced plasticity of GCs at perforant path synapses and decreased cell activity
 * Chronic fluoxetine increases cell activity and plasticity in cortical pyramidal neurons (Maya Vetencourt et al 2008)
 * After chronic fluoxetine, GCs de-differentiate (Kobayashi et al 2017 - not correct reference. maybe Inoto 2015)
 * Chronic fluoxetine decreases expression of mature GC markers (calbindin, desmoplakin, tryptophan-2,3-dioxygenase and type I interleukin-1 receptor. Increased GC excitability in fluoxetine-treated mice.
 * Chronic fluoxetine may enhance GC plasticity (kobayashi 2010)
 * possible mech: enhancement of serotonergc signaling: depletion of 5HT1AR s on gc LEADS TO LOSS OF BEHAVIORAL RESPONSE TO CHRONIC SSRI tx. Restoring 5HT1ARs on GC in deficient mice mimics antidepressant effect after chronic ssri TX (Samuels et al 2015)
 * 5HT1AR
 * 5HT1AR is assoc with downstream pathways (Rojas and Fielder 2016).
 * Linked to synaptogenesis and increased dendritic spine density in postnatal development (Mogha, Guariglia, Debata, Wen, Banerjee 2012)
 * May mediate induced structural, synaptic plasticity in the GC
 * 2.2 Granule Cell dysfunction in models of depression and its comorbidities
 * Chronic stress, steroids
 * Chronic stress suppresses perforant path LTP (Bodnoff et al 1995; alfarez, joels, krugers 2003)
 * GC spine density is significantly reduced in susceptible mice (Gu et al 2018; figure 1)
 * Chronic corticosterone tx -> similar decreased spine density (Bodnoff et al 1995; Alfarez et al 2003)
 * GC express both mineralocorticoid and glucocorticoid receptors (Reul and deKloet 1985; Joels 2007). Implies sensitivity to circulating steroids
 * Hippocampus participates in regulating the hypothalamic-pituitary-adrenal axis. GCs could initiate hippocampal mediated inhibition of that axis (Joankord + Herman 2008)
 * GC are susceptible to damage by elevated stress hormone levels (McEwen 1999)
 * Stress affects excitability of GC: AMPA receptor mediated currents are increased by corticosterone in stressed rats (Karst and Joels 2003)
 * GCs in Anxiety-like behavior
 * Manipulation of GC engrams: activation of specific subset of GCs by foot shock. Optogenetic activation of same GC cluster in non-stressful context results in fear/anxiety-like behavior (Liu et al 2012; Denny et al 2014)
 * Optogenetic inhibition of GC engrams representing fearful experience suppress fear freezing during memory recall. Therefore specific GC engrams encode and retrieve fearful memories (Denny et al 2014)
 * Activation of a non-fearful engram in fear context associates original memory with anxiety, so GC engrams are plastic (Ramirez 2013)
 * Can also undergo a switch in valence. Fear-related engrams activated during a rewarding context makes mice switch behavioral response to the one associated with rewarding memory. Then, when reexposed to the initial frightening environment, mice respond as if the rewarding context was there. DC engrams can thus be switched to different valence.
 * Hippocampus projects to amygdala, PFC. aLSO ASSOCIATED WITH STRESS, depression, anxiety. vaLENCE Switching isn't seen in the basolateral amygdala, suggests BLA cells are committed to drive either fear or reward, but not both (Redondo 2014). Learned fear is prepresented by hippocampal output to the BLA; innate anxiety: hipp -> lateral hypothalamus (Jimenez 2018). Switching emotional valence may be possible in other limbic areas innervated by the hippocampus (e.g. lateral hypothalamus, PFC)
 * Optogenetically reactivating positive DG engrams (activated from past positive experience) rescues stress-induced depressive like behavior. possible activation of hippocampus-BLA-NAc circuit, sparing the PFC (Ramirez et al 2013)
 * GCs mediate innate and learned anxiety, can switch respresentations of fearful and rewarding valences. DG can thus regulate neuronal circuits mediaating diverse emotional behaviors from depressive states to antidepressant response.
 * Newborn granule cells
 * Within 2-3 weeks of initial proliferation, nGCs exhibit mature GC morphology (Zhao, Teng, Summers, Ming, Gage 2006).
 * nGCs initially activated by GABA-ergic inputs from local interneurons. then excitatory glutamatergic input and output to CA2, CA3 (Zhao et al 2006; Llorens-Martin, Jorado Arjona, Avila, Hernandez 2015) and hilar interneurons and mossy cells (Toni et al 2008).
 * By 6 weeks, nGCs are hyperexcitable, have enhanced synaptic plasticity, and low threshold for LTP induction. Prolonged maturation develops mature physological properties. (Schmidt-Heiber, Jonas, Mischofberger 2004; Zhao et al 2006; Ge, Yang, Hsu, Ming, Song 2007; mING AND Song 2011; Danielson et al 2016; Tannenholz, Hen, Khierbek, 2016)
 * Numer of nGCs in rat: 9000 cells/day = 6-12% of gc population number of GC generated in a month= 62% entorhinal cortex excitatory projecting cells, 28% as large as the efferent ca3 pyramidal cels: nGCs thus have a large role in DG function and behavior (Cameron and McKay 2001)
 * Neurogenesis inhibition by irratiation impairs spatial pattern separation (Clelland 2009), and anxiety and depression-like behavior (Snyder, Soumier, Brewer, Pickel, Cameron 2011). Depression in rats following inhibition of neurogenesis by toxin (Mateus-Pinhiero 2013). Direct activation of neurogenesis in mice alleviates depression and anxiety-like behavior (Tunc-Ozcan 2019).
 * Neurogenesis is stress responsive
 * Stress decreases neurogenesis through the HPA axis, glucocorticoids (Sapolsky, Krey, McEwen 1985; Surget 2011; Lehmann, Brachman, Martinowich, Schloesser, Herkenham, 2013).
 * Stress paradigms: chronic mild stress (Surget 2008, 2011; Tanti 2013; Culig 2017), social defeat stress (Lehmann 2013, Mouri 2018), restraint stress (Ramirez et al 2015), social isolation (Miggio et al 2019), early life stress (Mirescu, Peters, Gould 2004) and chronic corticosterone treatment (David et al 2009).
 * Direct enhancement of neurogenesis improved behaioral responses to stress (Culig 2017, Anacker 2018). Increased neurogenesis also induced and associated with antidepressant effects after exercise (van Praag, Kempermann, Gage 1999), learning (Gould, Beylin, Tanapat, Reeves, Shors, 1999) environmental enrichment (Kempermann, Kuhn, Gage 1997; Young, Lawlor, Leone, Gragunow, During 1999), antidepressant tratment (Santarelli 2003, Surget 2008, Tunc Ozcan 2019).
 * Antidepressant effect of neurogenesis is debated (Surget 2008, Bessa 2009, David 2009, Nollet 2012). The effect of SSRIs may be indep of neurogenesis, and fluoxetine might only increase neurogenesis in young mice (Couillard-Despres 2009)
 * Chronic fluoxetine accelerates nGC maturation (Wang, David, Monckton, Battaglia, Hen 2008), but decreases maturation of mature GCs (Kobayashi 2010), so antidepressants might cause different effecs on mature and nGCs.
 * Attenuated neurogenesis is not correlated with depression-like outcomes (Vollmayr, Simonis, Weber, Hen 2003; Anacker 2018; Tunc Ozcan 2019)
 * How Neurogenesis responds to environmental cues to alter behavior
 * Anacker 2018: chemogenetic inhibition of nGC in ventral DG during subthreshold stress. Led to increased mature GC activity, and depression and anxiety-like behaviors post stress. induction of neurogenesis -> antideressant-like phenotype. Showed resilience to social defeat, reversed by reduced neurogenesis.
 * Neugoenesis-induced GC inhibition is pathway specific
 * EC-DG stimulation is antidepressive, mediated by neurogenesis (Yun 2018)
 * Result of nGC activation in the DG depends on the origin of incoming afferents from the EC (Luna 2019) Optogenetic silencing og the nGC had opposite effects on the lateral vs medial perfornt path-evoked GC responses.
 * Lateral perforant path inputs cause nGCs to exert monosynaptic inhibition on mature GCs. Mediated by groupII metabotropic gluamate recetpros.
 * Medial perforant path inputs cause nGCs to excite mature GCs via extrasynaptic NR3-containing NMDA receptors.
 * Dichotomy may rapidly shift the balance between contextual information (lateral perforant path) and spatial information (medial perforant path). Sparse coding may allow for context distinction in response to environmental cues, which may be impaired in anxiety-and depression-like states.
 * Role in humans is debated
 * 700 nerons are generated per day, decreasing with age (Bo>20ldrini 2018, Moreno-Jimenez 2019)
 * 35% of the whole DG undergoes replacement (>3x more than the rat DG) Spalding et al 2013)
 * Magnitude is debated (Cipriani 2018; Sorrells 2018; Moreno-Jimenez 2019).
 * Inhibitory interneurons in the DG in depression models
 * GCs get extensive cortical excitatory input from the perforant path, but are mostly silent bc of inhibitory input.
 * >20 types of interneurons in the neocortex and hippocampus (Klausberger and Somogyi 2008).
 * Most inhibitory interneurons of the DG are in the hilar subgranular zone (Amaral 2007).
 * There are 25x as many GCs as hilar cells in the rat (West 1991, Rapp and Gallagher 1996). 11x as many in the human, suggesting interneurons are more important in the human (Harding, Halliday, Kril 1998)
 * DG inhibitory system regulates mood
 * Tonic inhibition and inhibitory bursts control the excitatory threshold of the GC and sparse activation (Hosp 2014).
 * Altering the inhibition balance directly impacts behavior. Anacker 2018: inhibiting the ventral DG's GCs exerts stress resilience in mice.
 * in humans: inhibition by hippocampal GABAergic cells (but not cortical cells) suppresses unwanted thoughts (Schmitz, Correia, Ferreira, Prescot, Anderson 2017).
 * Chronic stress reduces GABA concentrations (Chronli 2017) and number of GABAergic interneurons (Czeh 2015) in rat hippocampi. [So is GABA good or bad?]
 * >5 classes of GABA-ergic interneurons including axo-axonic and MOPP (molecular layer perforant path-associated cells) with soma in the molecular layer, HICAP (hilar commissural-associated pathway-related cells) and HIPP (hilar perforant path-associated) cells with somas in the hipus, and basket cells with somas in the subgranular zone.  Distinct morphology, physiology (Freund and Buzsaki 1996). Only cholecystokinin (CCK) and Parvalbimin (PV)-expressing basket cells. are linked to depressive-like behaviors and action of antidepressants (Medrihan 2017, Sagi 2019)
 * Large pyramidal soma (2x that of a GC), spineless bitufted dendrites. Simgle, principal aspiny apital dendrite directed into the morlecular layer, divided into branches that extend on the polymorphic cell layer allows them to integraate extensive perforant path inputs and commisural associational inputs. Basket cells have several principal basal dendrites allowing them to integrate the inputs that target the DG hilus. their axons span into all laers of the DG GC and densely target somas of the proximal dendrite shafts of the GC to form a terminal plexus confined to the GC layer (Amaral 2007, Pelkey 2017). Basket cell axons stretch and branck up to 1.5mm from cell body, allowing a single basket cell to inhibit as many as 10k GCs (Amaral 2007).
 * CCK basket cells
 * CCK expressing basket cells make and release CCK.
 * Fire accomodating spikes at moderate frequencies with high membrane input resistance (Bartox and Elgueta 2012). Postsynaptic expression of calcium impermeable GluR2-containing AMPA receptors may explain why these basket cells do not have synaptic plasticity [WHY?] (Nissen, Szabo, Somogyi, Lamsa 2010).
 * CCK is present in GI system and brain, incl high amts in limbic system and hippocampus (Canderhaegen, Signeay, Gepts 1975)
 * CCK Induces anxiety and fear behavior
 * CCK-B receptor is implicated (review: Wang, Wong, Speiss, Zhu 2005)
 * CCK-B receptor is expressed on PV cells in the DG. Neuroendocrine communication between hippocampal basket cells may be critical in fear and anxiety.
 * CCK-expressing interneurons unidirectionally inhibit parvalbumin-expressing basket cells through GABA-A receptors to suppress fast-spiking activity (Armstrong and Soltesz 2012)
 * CCK cells are only cells in the DG that are regulated by neurobodulators on both pre and post synaptic receptors.
 * Key presynaptic regulators
 * Endocannabinoids
 * CCK cells have the highest expression of presynaptic endocannabinoid receptor 1 (CB1) in the hippocampus
 * CB1 is activated upon endocannabinoids released from activated glutamatergic cells including GCs or mossy cells.
 * CB1 is a Gi/o-coupled receptor, its activation in DG CCK cells induces inhibition of GABA release (Katona 1999, Bartox and Elgueta 2012).
 * MDD patients have higher frequency of mutant allele of CNR1, which encodes the CB1 receptor (Monteleone 2010). In mice, CB1 KO mice have a depressive-like phenotype accompanied with decreased hippocampal BDNF levels (Aso 2008) and impaired neurogenesis (Jin 2004). Chronic stress assoc with decreased CB1 receptor signaling in the hippocampus (Hu, Zhang, Czeh, Zhang, Flugge 2011). Activation of CB1 by HU210 [??] induces DG neurogenesis and has antidepressant, and anxiolytic effects (Jiang 2005).
 * CB1 activation in the hippocampus has biphasic behavioral effects: low doses are anxiolytic (Rubino 2008, Zarrindast, Nasehi, Piri, Bina 2010), higher dosis have no or anxiogenic effects (Roohbaksh 2007, Rubino 2008). May be due to favorable activation of CB1 on CCK neurons at low doses and on glutamtergic neurons at higher doses.
 * Serotonin (5HT)
 * CCK cells are highly responsive to 5HT. Has pre and post-synaptic effects Mediated by receptors including 5HT1B, 2A, 2C, 3A (Gruber 2015, Medihan 2017)
 * CCK-expressing basket cells are highly responsive to 5HT projections from raphe nucleus to hippocampus (Leranth and Hajszan 2007).
 * When pre or postsynaptic 5HT receptors are activated, DG CCK basket cell activity decreases, allowing PV cells to be disinhibited and exert increased inhibition on GCs (Medrihan et al 2017)
 * a
 * a
 * a
 * a
 * a
 * a
 * a
 * a
 * a
 * a
 * aa
 * aa

__NOINDEX__