Loss of Catecholaminergic Neuromodulation of Persistent Forms of Hippocampal Synaptic Plasticity with Increasing Age

Abstract

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 (>24 h), 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 apparent 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. 2 h could be strengthened into persistent (>24 h) 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 behavioral thresholds for novelty and motivation that emerge with increasing age that impact, in turn, on learning efficacy.

Keywords: LTP; beta-adrenergic; dentate gyrus; dopamine D1/D5; in vivo; noradrenaline; rat; synaptic plasticity.

Figure 1

Basal synaptic transmission in the dentate gyrus of middle-aged rats is not influenced by agonist activation of D1/D5 or beta-adrenergic receptors. In vehicle-treated middle-aged animals, test-pulse stimulation evoked stable fEPSP and population spike (PS) responses for the duration of the monitoring period. (A,B) Treatment with the D1/D5 receptor agonist, chloro-PB (41.25 μg, 82.5 μg) has no effect on the PS (A) or the fEPSP (B) compared to vehicle-treated controls. (C,D) Treatment with the beta-adrenergic receptor agonist, isoproterenol (20 μg, 40 μg) has no effect on the PS (C) or the fEPSP (D) compared to vehicle-treated controls. The arrow in the graphs indicates time-point of injection. Line-breaks indicate changes in time-scale. (E) Analog examples depict potentials obtained in a vehicle experiment (left traces), in the presence of 41.25 μg of chloroPB (Middle traces) or 82.5 μg chloroPB (right traces) at: (i) 5 min prior to injection; (ii) 5 min post-injection; and (iii) 24 h post-injection. Vertical scale bar: 2 mV, horizontal scale bar: 8 ms. (F) Analog examples depict potentials obtained in a vehicle experiment (left traces), in the presence of 20 μg of isoproterenol (Middle traces) or 40 μg isoproterenol (right traces) at: (i) 5 min prior to injection; (ii) 5 min post-injection; and (iii) 24 h post-injection. Vertical scale bar: 2 mV, horizontal scale bar: 8 ms.

Figure 2

Agonist activation of dopamine D1/D5 receptors prolongs synaptic potentiation in the dentate gyrus of young but not middle-aged rats. (A,B) In vehicle-treated middle-aged animals weak high-frequency stimulation (wHFS) results in short-term potentiation (STP) of PS (A) and fEPSP (B) that lasted for ca. 2 h. When wHFS was applied in the presence of the D1/D5-receptor agonist chloroPB (41.25 μg, 82.5 μg) STP occurs that is not significantly different from vehicle-treated controls. (C,D) Vehicle-treated young animals that receive wHFS, respond with STP of PS (C) and fEPSP (D) that lasts for ca. 2 h, whereas wHFS given in the presence of chloroPB (41.25 μg) results in long-term potentiation (LTP) that lasts for at least 25 h. The arrows in the graphs indicate the time-point of injection, or wHFS. Line-breaks indicate changes in time-scale. (E) Analog examples depict potentials that were evoked during a control experiment (left traces), in the presence of 41.25 μg of chloroPB (Middle traces) or 82.5 μg chloroPB (right traces) in middle-aged animals. Potentials were obtained: (i) 5 min prior to wHFS; (ii) 5 min post-wHFS; and (iii) 24 h post-wHFS. Vertical scale bar: 2 mV, horizontal scale bar: 8 ms. (F) Analog examples depict potentials obtained during a vehicle experiment (left traces), or in the presence of 41.25 μg of chloroPB (right traces) in young animals, Responses were obtained: (i) 5 min prior to wHFS; (ii) 5 min post-wHFS; and (iii) 24 h post-wHFS. Vertical scale bar: 2 mV, horizontal scale bar: 8 ms.

Figure 3

Agonist activation of beta-adrenergic receptors prolongs synaptic potentiation in the dentate gyrus of young, but not middle-aged, rats. (A,B) In vehicle-treated middle-aged animals wHFS results in STP of PS (A) and fEPSP (B) that lasts for ca. 2 h. wHFS in the presence of the beta-adrenergic receptor agonist, isoproterenol (20 μg, 40 μg), results in STP that is not significantly different from vehicle-treated controls. Line breaks indicate change in time scale. (C,D) Vehicle-treated young animals that received wHFS, express STP of PS (C) and fEPSP (D) that lasts for ca. 2 h. wHFS in the presence of isoproterenol (20 μg) results in LTP that lasts for at least 25 h. The arrows in the graphs indicate the time-point of injection, or wHFS. Line-breaks indicate changes in time-scale. (E) Analog examples depict potentials from vehicle experiment (left traces), in the presence of 20 μg of isoproterenol (Middle traces) or 40 μg isoproterenol (right traces) in middle-aged animals obtained: (i) 5 min prior to wHFS; (ii) 5 min post-wHFS; and (iii) 24 h post-wHFS. Vertical scale bar: 2 mV, horizontal scale bar: 8 ms. (F) Analog examples depict potentials from vehicle experiment (left traces), in the presence of 20 μg of isoproterenol (right traces) in young animals obtained: (i) 5 min prior to wHFS; (ii) 5 min post-wHFS; and (iii) 24 h post-wHFS. Vertical scale bar: 2 mV, horizontal scale bar: 8 ms.

Figure 4

LTP is unaltered in middle-aged compared to young rats. Novel spatial learning facilitates LTP expression in middle-aged rats. (A,B) Strong high-frequency stimulation (HFS) results in LTP of the PS (A) and fEPSP (B) that lasts for at least 25 h in both young and middle-aged rats. Test-pulse stimulation results in equivalently stable basal synaptic transmission in both age groups. (C,D) wHFS resulted in STP of the PS (C) and fEPSP (D) in the dentate gyrus of middle aged rats. Coupling wHFS with novel spatial exploration of a holeboard facilitated STP into LTP that lasted for at least 25 h. The arrow in the graphs indicates the time-point of HFS/wHFS. Line-breaks indicate changes in time-scale. (E) Analog examples depict potentials from young animals (left traces) and middle-aged animals (right traces): (i) 5 min prior to HFS; (ii) 5 min post-HFS; and (iii) 24 h post-HFS. Vertical scale bar: 2 mV, horizontal scale bar: 8 ms. (F) Analog examples depict potentials from middle-aged animals that received wHFS only (left traces) and from middle-aged animals that received wHFS during novel holeboard exploration (right traces) obtained: (i) 5 min prior to wHFS; (ii) 5 min post-wHFS; and (iii) 24 h post-wHFS. Vertical scale bar: 2 mV, horizontal scale bar: 8 ms.