Neuromodulation of the feedforward dentate gyrus-CA3 microcircuit

The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval

Aminergic modulation of hippocampal synaptic plasticity in health and disease

Synaptische Plastizität ist ein zellulärer Prozess, der Lernen und Gedächtnisbildung ermöglicht. Abhängig von Alter und Gesundheitszustand können das Erwerben von Gedächtnis sowie die Stabilität vom Erlernten variieren. Hier spielen Neuromodulatoren eine wichtige Rolle. In dieser Studie wurde der Einfluss spezifischer Rezeptor-Subformen auf synaptische Plastizität im Gyrus Dentatus der Ratte untersucht. In jungen Ratten (2-4 Monate) beeinflusst der serotonerge 5-HT$_4$ Rezeptor nur schwach die Exprimierung von Langzeit Potenzierung (LTP). Aktivierung der beta-adrenergen oder dopaminergen Rezeptoren der D1-Familie vereinfacht die Entstehung von LTP. Diese Eigenschaft geht in älteren Tieren (8-14 Monate) verloren. In beta-amyloid injizierten (Alzheimer Model) Tieren geht zudem LTP-Exprimierung verloren. Koaktivierung der beta-adrenergen und dopaminergen Rezeptoren, durch ein Verhaltensprotokoll oder pharmakologisch, ermöglicht erneut eine leichtere Entstehung von LTP in beiden Kohorten

The 5‐hydroxytryptamine ₄ receptor enables differentiation of informational content and encoding in the hippocampus

Long‐term synaptic plasticity, represented by long‐term depression (LTD) and long‐term potentiation (LTP) comprise cellular processes that enable memory. Neuromodulators such as serotonin regulate hippocampal function, and the 5‐HT(4)‐receptor contributes to processes underlying cognition. It was previously shown that in the CA1‐region, 5‐HT(4)‐receptors regulate the frequency‐response relationship of synaptic plasticity: patterned afferent stimulation that has no effect on synaptic strength (i.e., a θm‐frequency), will result in LTP or LTD, when given in the presence of a 5‐HT(4)‐agonist, or antagonist, respectively. Here, we show that in the dentate gyrus (DG) and CA3 regions of freely behaving rats, pharmacological manipulations of 5‐HT(4)‐receptors do not influence responses generated at θm‐frequencies, but activation of 5‐HT(4)‐receptors prevents persistent LTD in mossy fiber (mf)‐CA3, or perforant path‐DG synapses. Furthermore, the regulation by 5‐HT(4)‐receptors of LTP is subfield‐specific: 5‐HT(4)‐receptor‐activation prevents mf‐CA3‐LTP, but does not strongly affect DG‐potentiation. These data suggest that 5‐HT(4)‐receptor activation prioritises information encoding by means of LTP in the DG and CA1 regions, and suppresses persistent information storage in mf‐CA3 synapses. Thus, 5‐HT(4)‐receptors serve to shape information storage across the hippocampal circuitry and specify the nature of experience‐dependent encoding. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc

Loss of catecholaminergic neuromodulation of persistent forms of hippocampal synaptic plasticity with increasing age

Neuromodulation by means of the catecholaminergic system is a key component of motivation-driven learning and behaviorally modulated hippocampal synaptic plasticity. In particular, dopamine acting on D1/D5 receptors and noradrenaline acting on beta-adrenergic receptors exert a very potent regulation of forms of hippocampal synaptic plasticity that last for very long-periods of time (>24h), and occur in conjunction with novel spatial learning. Antagonism of these receptors not only prevents long-term potentiation (LTP) and long-term depression (LTD), but prevents the memory of the spatial event that, under normal circumstances, leads to the perpetuation of these plasticity forms. Spatial learning behavior that normally comes easily to rats, such as object-place learning and spatial reference learning, becomes increasingly impaired with aging. Middle-aged animals display aging-related deficits of specific, but not all, components of spatial learning, and one possibility is that this initial manifestation of decrements in learning ability that become manifest in middle-age relate to changes in motivation, attention and/or the regulation by neuromodulatory systems of these behavioral states.Here, we compared the regulation by dopaminergic D1/D5 and beta-adrenergic receptors of persistent LTP in young (2-4 month old) and middle-aged (8-14 month old) rats. We observed in young rats, that weak potentiation that typically lasts for ca. 2h could be strengthened into persistent (>24h) LTP by pharmacological activation of either D1/D5 or beta-adrenergic receptors. By contrast, no such facilitation occurred in middle-aged rats. This difference was not related to an ostensible learning deficit: a facilitation of weak potentiation into LTP by spatial learning was possible both in young and middle-aged rats. It was also not directly linked to deficits in LTP: strong afferent stimulation resulted in equivalent LTP in both age groups. We postulate that this change in catecholaminergic control of synaptic plasticity that emerges with aging, does not relate to a learning deficit per se, rather it derives from an increase in behavioural thresholds for novelty and motivation that emerge with increasing age that impact, in turn, on learning efficacy

ANPC workshop reports: Feeling seedy in the Hunter

Volume: 27Start Page: 36End Page: 3

A dentate gyrus– CA3 inhibitory circuit promotes evolution of hippocampal-cortical ensembles during memory consolidation

AbstractMemories encoded in the dentate gyrus (DG) – CA3 circuit of the hippocampus are routed from CA1 to anterior cingulate cortex (ACC) for consolidation. Although CA1 parvalbumin inhibitory neurons (PV INs) orchestrate hippocampal-cortical communication, we know less about CA3 PV INs or DG – CA3 principal neuron – IN circuit mechanisms that contribute to evolution of hippocampal-cortical ensembles during memory consolidation. Using viral genetics to selectively mimic and boost an endogenous learning-dependent circuit mechanism, DG cell recruitment of CA3 PV INs and feed-forward inhibition (FFI) in CA3, in combination with longitudinal in vivo calcium imaging, we demonstrate that FFI facilitates formation and maintenance of context-associated neuronal ensembles in CA1. Increasing FFI in DG – CA3 promoted context specificity of neuronal ensembles in ACC over time and enhanced long-term contextual fear memory. In vivo LFP recordings in mice with increased FFI in DG – CA3 identified enhanced CA1 sharp-wave ripple – ACC spindle coupling as a potential network mechanism facilitating memory consolidation. Our findings illuminate how FFI in DG – CA3 dictates evolution of ensemble properties in CA1 and ACC during memory consolidation and suggest a teacher-like function for hippocampal CA1 in stabilization and re-organization of cortical representations.</jats:p

105P Dotętnicze leczenie chemiczne chorych z pierwotnymi, nieoperacyjnymi nowotworami złośliwymi ośrodkowego układu nerwowego

W grupie chorych z pierwotnymi guzami ośrodkowego układu nerwowego, którzy nie mogli być operowani z powodu zaawansowania nowotworu zastosowano chemioterapię przeztętniczą. Ta forma leczenia pozwala na uzyskanie największego stężenia cytostatyku w tkance nowotworowej.U 11 chorych z nieoperacyjnymi pierwotnymi guzami ośrodkowego układu nerwowego zastosowano chemioterapię przeztętniczą BCNU. Wszyscy chorzy byli cewnikowaniui poprzez tętnicę udową. Mikrokrater umieszczano w odpowiedniej tętnicy mózgowej, zależnie od lokalizacji guza. BCNU podawano w 5% glukozie w objętości 50 ml, w dawkach 160–180 mg/m2. Po 3 cyklach w/w leczenia chorzy otrzymywali BCNU w dawkach 120–140 mg/m2. Odpowiedź na zastosowaną chemioterapię oceniano w badaniu tomografii komputerowej, które wykonywano przed leczeniem, 24h i 3 tygodnie po podaniu BCNU. W badanej grupie chorych obserwowano objawy uboczne pozahematologicznie: gorączka (3 chorych), afazja czuciowa (1 chory), bóle głowy (3 chorych), przejściowe zaburzenia widzenia (1 chory), porażenie połowiczne (1 chory), powiększenie strefy obrzęku wokół guza (1 chory), zwężenie tętnicy po mikrokrateryzacji (1 chory). W wyniku zastosowanej chemioterapii lokoregionalnej stwierdzono u 4 chorych PR, 4 chorych SD, 3 chorych PD. Wśród 11 chorych 9 (87,3%) zmarło a 2 (12,7%) żyje. Średni czas przeżycia wynosił 2,6 miesiąca (od 0,5 do 29,6 miesiąca)