Mark G. Packard

Amygdala Is Critical for Stress-Induced Modulation of Hippocampal Long-Term Potentiation and Learning

Stress is a biologically significant factor shown to influence synaptic plasticity and memory functioning in the hippocampus. This study examined the role of the amygdala, a brain structure implicated in coordinating stress behaviors and modulating memory consolidation, in mediating stress effects on hippocampal long-term potentiation (LTP) and memory in rats. Electrolytic lesions of the amygdala effectively blocked the adverse physiological and behavioral effects of restraint and tailshock stress, without impeding the increase in corticosterone secretion to stress. Physiologically, hippocampal slices from stressed animals exhibited impaired LTP relative to slices from unstressed control animals, whereas hippocampal slices from stressed animals with amygdalar lesions exhibited normal LTP. Behaviorally, stressed animals were impaired in retention of a hippocampal-dependent hidden platform version of the Morris water maze task, and this impairment was blocked by amygdalar lesions. In a fixed location–visible platform water maze task that can be acquired by independent hippocampal and nonhippocampal memory systems, stress enhanced the use of nonhippocampal-based memory to acquire the task. These results indicate that an intact amygdala is necessary for the expression of the modulatory effects of stress on hippocampal LTP and memory.

Dissociation of hippocampus and caudate nucleus memory systems by posttraining intracerebral injection of dopamine agonists

The effect of posttraining intracerebral injections of the indirect dopamine (DA) agonist d-amphetamine, the direct D2 agonist LY 171555, and the direct D1 agonist SKF-38393 on the acquisition of two 8-arm radial maze tasks were examined. On a win-stay task, a light cue signaled the location of food in 4 randomly selected maze arms on each trial, and animals were required to visit each of the lit arms twice within a trial. Posttraining intracaudate injection of d-amphetamine (10.0 and 15.0 micrograms), LY 171555 (2.0 micrograms), and SKF-38393 (5.0 micrograms) all improved win-stay acquisition in relation to saline-injected controls. In contrast, posttraining intrahippocampal injection of DA agonists had no effect on win-stay acquisition. On a win-shift task, rats were allowed to obtain food from 4 randomly selected maze arms, followed by a delay period in which they were removed from the maze. They were returned to the maze for a retention test in which only those arms that had not been visited before the delay contained food. Posttraining intrahippocampal (but not intracaudate) injection of d-amphetamine (5.0 micrograms), LY 171555 (2.0 micrograms), and SKF-38393 (5.0 micrograms) all improved win-shift retention in relation to saline-injected controls. The results demonstrate a double dissociation of hippocampus and caudate nucleus memory functions and show that posttraining injection of both D1 and D2 agonists modulate the memory processes subserved by both hippocampus and caudate nucleus.

The dopaminergic mesencephalic projections to the hippocampal formation in the rat

1. The dopaminergic mesencephalic neurons projecting to the hippocampal formation are distributed in three cell groups: A8 region in the retrorubral field, A9 region in the substantia nigra and A10 region in the ventral tegmental area. 2. Anterograde and retrograde tract-tracing techniques combined with immunohistochemical procedures indicate a topographical organization of mesencephalic dopaminergic projections towards the hippocampal formation. 3. Electrophysiological evidence suggest that dopaminergic mesencephalic neurons could have a regulatory role in suppressing hippocampal excitability. 4. The functional significance of the mesohippocampal dopaminergic system is largely unknown, although it was suggested that this projection could have a role in methamphetamine-produced hypermotility and in modulation of memory processes.

Anterograde and retrograde tracing of projections from the ventral tegmental area to the hippocampal formation in the rat

Employing anterograde tracing with Phaseolus vulgaris-leucoagglutinin (PHA-L), and a triple labeling protocol using retrogradely transported fluorescent tracers, we examined the projections from the ventral tegmental area (VTA-A10) to the hippocampal formation (HF) in the rat. Injections of PHA-L into VTA resulted in labeling in the ventral subiculum (stratum oriens and molecular layer) and in the adjacent CA1 field (stratum oriens, pyramidal, suprapyramidal and molecular layers) of HF. Additional labeling was observed in the stratum oriens of CA3 and in the hilus of fascia dentata. In the dorsal HF labeling was present in the subicular and CA1 field polymorphic layers. The distribution of VTA neurons projecting to the HF was also examined by injecting retrograde fluorescent tracers (Fluoro Gold, Fast Blue, and Nuclear Yellow) in several hippocampal areas. The most abundant VTA-HF projections originate from the upper and lower edges and the lower half of the VTA. These terminal fields in the HF match with the hippocampal areas projecting to the nucleus accumbens. The VTA, via projections to interconnected regions of the HF and nucleus accumbens, may modulate the hypothesized functional link between the limbic system and basal ganglia.

Posttraining estradiol injections enhance memory in ovariectomized rats : Cholinergic blockade and synergism

The present experiments examined acute posttraining estrogenic influences on memory in ovariectomized rats. In experiment 1 rats received a single 8-trial (30-s ITI) training session with a submerged escape platform located in the same quadrant of a circular water maze on all trials. Following trial 8, rats received a posttraining intraperitoneal injection of either an estradiol-cyclodextrin inclusion complex (0.1, 0.2, or 0.4 mg/kg) or saline. On a retention test session 24 h later, the escape latencies of rats given injections of estradiol (0.2 mg/kg) were significantly lower than those of saline-treated rats, indicating an enhancement of memory. Injections of estradiol delayed 2 h posttraining did not affect retention, demonstrating a time-dependent effect of estradiol on memory storage processes. In experiment 2a, posttraining injections of the cholinergic muscarinic receptor antagonist scopolamine (0.4 mg/kg) impaired memory in ovariectomized rats. In experiment 2b, the memory-enhancing effect of estradiol (0.2 mg/kg) was blocked by concurrent posttraining administration of a subeffective dose (0.1 mg/kg) of scopolamine, suggesting an interaction between estradiol and muscarinic cholinergic systems in memory modulation. In experiment 3a, posttraining injections of the cholinergic muscarinic receptor agonist oxotremorine (0.2 mg/kg) enhanced memory in ovariectomized rats. In experiment 3b, concurrent posttraining injection a subeffective dose of estradiol (0.1 mg/kg) and a subeffective dose of oxotremorine (0.1 mg/kg) enhanced memory, indicating a synergistic effect of estradiol and muscarinic receptor activation on memory.

Affective modulation of multiple memory systems

The hippocampus and caudate nucleus are anatomical components of relatively independent memory systems and recent research has focused on the nature of the interaction between these two systems. The amygdala exerts a general modulatory influence on memory storage processes related, in part, to an organisms level of affective or emotional arousal. Moreover, affective state can influence the use of different memory systems, and the amygdala may mediate this effect of emotion on memory. Recent evidence indicates that the amygdala modulates the separate types of memory mediated by the hippocampus and caudate nucleus. Recent human brain imaging studies also point to both sex- and hemisphere-related asymmetries in amygdala participation in emotionally influenced memory.

Posttraining estrogen and memory modulation.

The present paper provides a review of recent research carried out in this laboratory investigating the effects of posttraining peripheral and intrahippocampal injection of estradiol on memory in rats, and estradiol-acetylcholine interactions in memory modulation. Ovariectomized rats received an eight-trial training session in a hippocampal-dependent hidden platform water maze task. Immediately following training, rats received a posttraining peripheral or intrahippocampal injection of estradiol-cyclodextrin complex or vehicle. Twenty-four hours later rats were returned to the maze for a retention test session, and latency to escape was used as a measure of memory for the previous days training. Peripheral posttraining injection of estradiol enhances memory relative to vehicle-treated rats. Injections of estradiol given 2 h posttraining has no effect on retention, indicating a time-dependent effect of estradiol on memory storage processes. A time-dependent memory enhancing effect of posttraining intrahippocampal injections of estradiol has also been observed in both male and ovariectomized female rats. The memory enhancing effect of peripheral posttraining injection of estradiol in ovariectomized rats is blocked by a subeffective dose of the acetylcholine muscarinic receptor antagonist scopolamine, suggesting that estradiol interacts with cholinergic systems in memory modulation. Concurrent peripheral posttraining injection of a subeffective dose of estradiol and a subeffective dose of the cholinergic agonist oxotremorine produces a synergistic memory enhancing effect. The findings suggest that: (1) estradiol selectively influences memory storage independent of an effect on nonmnemonic processes, (2) the hippocampus is a potential neuroanatomical site of action mediating estrogenic effects on memory, and (3) estradiol interacts with cholinergic systems in memory modulation.

Intra-hippocampal estradiol infusion enhances memory in ovariectomized rats.

OVARIECTOMIZED adult Long—Evans rats received an eight-trial training session in a hippocampal-dependent hidden platform water maze task. Following trial 8, rats received an intra-hippocampal injection of estradiol in a water soluble cyclodextrin inclusion complex (1.0, 2.0 or 5.0 μg/0.5 μl), or saline. Twenty-four hours later, the retention test escape latencies of rats administered posttraining intra-hippocampal injections of estradiol (5.0 μg) were significantly lower than those of saline treated rats, indicating a memory-enhancing effect of estradiol. Injections of estradiol (5.0 μg) given 2 h post-training had no effect on retention, indicating a time-dependent effect of estradiol on memory storage processes.

Testosterone has rewarding affective properties in male rats: implications for the biological basis of sexual motivation.

Evidence from mammalian species, including humans, suggests that testosterone (T) enhances motivational aspects of sexual behavior, although the mechanism by which T exerts this effect is unknown. The hypothesis that increases in plasma T have rewarding affective properties was examined. Acute elevations of plasma T were induced in intact male rats by systemic administration of a recently developed testosterone-hydroxypropyl-beta-cyclodextrin inclusion complex that mimics pulsatile release of the hormone. In a conditioned-place-preference paradigm, rats displayed a preference for an environment previously paired with T administration (800 micrograms/kg and 1,200 micrograms/kg) as opposed to an environment paired with saline administration, indicating that T has rewarding affective properties. The findings suggest that T may enhance motivational aspects of mammalian sexual behavior by facilitating acquisition or expression of learned associations between environmental stimuli and sexual activity.

Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentanoic acid.

Rats received an 8-trial training session on a spatial or cued task in a water maze, followed by a posttraining intracerebral injection of AP5 or saline. On a retention test 24 hr later, latency to mount the escape platform was used as a measure of memory. Intrahippocampal (10 micrograms), but not intra-dorsal striatal (2, 5, or 10 micrograms), injection of AP5 impaired memory in the spatial task. In contrast, intra-dorsal striatal (2 micrograms), but not intrahippocampal (2, 5, or 10 micrograms) injection of AP5 impaired memory in the cued task. Intracerebral injections of AP5 delayed 2 hr posttraining were ineffective. The findings indicate a double dissociation of the roles of the hippocampus and dorsal striatum in memory, a role for N-methyl-D-aspartate receptor function in posttraining memory processes, and a glutamatergic modulation of both hippocampal and dorsal striatal memory processes, suggesting that different forms of memory may share a similar neurochemical basis.