Muscarinic cholinergic contribution to memory consolidation: with attention to involvement of the basolateral amygdala.

The central cholinergic system and muscarinic cholinergic receptor (mR) activation have long been associated with cognitive function. And degeneration of the cholinergic basal forebrain (CBF) neurons is a pronounced hallmark of Alzheimer's Disease (AD). However, CBF immunolesions as animal models of AD cholinergic degeneration have not replicated the robust memory deficits of nonselective excitotoxic lesions. The less studied cholinergic projections to the amygdala, which are affected in AD but unaffected by immunolesions, may be more important in memory storage than previously suspected. The sparing of these amygdalopetal projections may help explain the dissociation between excitotoxic and immunotoxic CBF lesions. The CBF projections to cortex have since been shown to be important for attentional processes, which may contribute indirectly to memory. Nonetheless, there are conditions under which their selective ablation produces clear memory deficits. For example, memory enhancement induced by posttraining basolateral amygdalar activation is ineffective when corticopetal cholinergic projections are lesioned. Moreover, posttraining cholinergic agonism enhances long-term memory. Such findings suggest that cholinergic innervation of the cortex may be particularly important during modulation of memory storage for stressful and/or arousing events. In concordance, mR agonism facilitates neuronal plasticity and can induce expression of memory-associated immediate early genes. The present article reviews the behavior, physiology and inducible genetic expression literatures which together suggest that the early CBF lesion data were not a red herring but rather that CBF projections not only to cortex but also to the amygdala may in fact have important neuromodulatory functions in memory consolidation processes.

Cholinergic modulation of memory in the basolateral amygdala involves activation of both m1 and m2 receptors.

Muscarinic cholinergic activation is a critical component of basolateral amygdala (BLA)-mediated modulation of memory consolidation. The receptor(s) mediating this activation during consolidation have not been elucidated. This study investigated the roles of muscarinic subtype 1 (m1) and subtype 2 (m2) receptors in memory enhancement, by post-training intra-BLA infusions of the non-selective muscarinic agonist oxotremorine. Rats received intra-BLA infusions of either oxotremorine alone (10 microg in 0.2 microl per side), oxotremorine together with the selective m1 antagonist telenzipine (1.7, 5.0, 17 or 50 nmol/side), oxotremorine with the selective m2 antagonist methoctramine (1.7, 5.0, 17 or 50 nmol/side), oxotremorine with a combination of the above doses of telenzipine and methoctramine, or only vehicle, immediately after inhibitory avoidance training. Performance on a 48-hour retention test was significantly enhanced in oxotremorine-treated rats relative to vehicle-infused controls. Intra-BLA co-infusion of oxotremorine with either telenzipine (5, 17 or 50 nmol/side) or methoctramine (17 or 50 nmol/side) blocked the oxotremorine-induced enhancement. Combinations of these antagonists did not act additively to block memory enhancement by oxotremorine. These findings indicate that modulation of memory consolidation induced by cholinergic influences within the BLA requires activation of both m1 and m2 receptor synapses. Plausible mechanisms for m1- and m2-mediated influences on BLA circuitry are discussed.

Memory retrieval impairment induced by hippocampal CA3 lesions is blocked by adrenocortical suppression.

There is evidence that in rats, partial hippocampal lesions or selective ablation of the CA3 subfield can disrupt retrieval of spatial memory and that hippocampal damage disinhibits hypothalamic-pituitary-adrenocortical (HPA)-axis activity, thereby elevating plasma levels of adrenocorticotropin and corticosterone. Here we report evidence that attenuation of CA3 lesion-induced increases in circulating corticosterone levels with the synthesis inhibitor metyrapone, administered shortly before water-maze retention testing, blocks the impairing effects of the lesion on memory retrieval. These findings suggest that elevated adrenocortical activity is critical in mediating memory retrieval deficits induced by hippocampal damage.

Glucocorticoid enhancement of memory consolidation in the rat is blocked by muscarinic receptor antagonism in the basolateral amygdala.

Glucocorticoid-induced memory enhancement is known to depend on beta-adrenoceptor activation in the basolateral amygdala (BLA). Additionally, inactivation of muscarinic cholinergic receptors in the rat amygdala blocks memory enhancement induced by concurrent beta-adrenergic activation. Together, these findings suggest that glucocorticoid-induced modulation of memory consolidation requires cholinergic as well as adrenergic activation in the BLA. Two experiments investigated this issue. The first experiment examined whether blockade of muscarinic cholinergic receptors in the BLA with atropine alters the memory-enhancing effects of the systemically administered glucocorticoid dexamethasone. Dexamethasone (0.3, 1.0 or 3.0 mg/kg, s.c.) administered to rats immediately after inhibitory avoidance training produced dose-dependent enhancement of 48-h retention. Concurrent bilateral infusions of the muscarinic cholinergic antagonist atropine (0.5 microg in 0.2 microL per side) into the BLA blocked the memory enhancement. The second experiment investigated whether the BLA is a locus of interaction between glucocorticoid and muscarinic activation. The specific glucocorticoid receptor (GR or type II) agonist RU 28362 (1.0, 3.0 or 10 ng) was infused into the BLA either alone or together with atropine immediately after training. The GR agonist produced dose-dependent memory enhancement and atropine blocked the memory enhancement. These findings indicate that muscarinic cholinergic activation within the BLA is critical for enabling glucocorticoid enhancement of memory consolidation and that enhancement of memory induced by GR activation in the BLA requires cholinergic activation within the BLA.

Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord.

The existence of multipotent progenitor populations in the adult forebrain has been widely studied. To extend this knowledge to the adult spinal cord we have examined the proliferation, distribution, and phenotypic fate of dividing cells in the adult rat spinal cord. Bromodeoxyuridine (BrdU) was used to label dividing cells in 13- to 14-week-old, intact Fischer rats. Single daily injections of BrdU were administered over a 12 d period. Animals were killed either 1 d or 4 weeks after the last injection of BrdU. We observed frequent cell division throughout the adult rodent spinal cord, particularly in white matter tracts (5-7% of all nuclei). The majority of BrdU-labeled cells colocalized with markers of immature glial cells. At 4 weeks, 10% of dividing cells expressed mature astrocyte and oligodendroglial markers. These data predict that 0.75% of all astrocytes and 0.82% of all oligodendrocytes are derived from a dividing population over a 4 week period. To determine the migratory nature of dividing cells, a single BrdU injection was given to animals that were killed 1 hr after the injection. In these tissues, the distribution and incidence of BrdU labeling matched those of the 4 week post injection (pi) groups, suggesting that proliferating cells divide in situ rather than migrate from the ependymal zone. These data suggest a higher level of cellular plasticity for the intact spinal cord than has previously been observed and that glial progenitors exist in the outer circumference of the spinal cord that can give rise to both astrocytes and oligodendrocytes.

Basolateral amygdala noradrenergic influence enables enhancement of memory consolidation induced by hippocampal glucocorticoid receptor activation.

Previously, we reported that bilateral excitotoxic lesions of the basolateral nucleus of the amygdala (BLA) block the enhancing effects of posttraining systemic or intrahippocampal glucocorticoid administration on memory for inhibitory avoidance training. The present study further examined the basis of this permissive influence of the BLA on hippocampal memory functioning. Immediate posttraining unilateral infusions of the specific glucocorticoid receptor agonist RU 28362 (11beta,17beta-dihydroxy-6, 21-dimethyl-17alpha-pregna-4,6-trien-20-yn-3-one; 3.0, 10.0, or 30.0 ng in 0.5 microliter) administered into the dorsal hippocampus of male Sprague-Dawley rats induced dose-dependent enhancement of 48-h inhibitory avoidance retention. Infusions of the beta-adrenoceptor antagonist atenolol (0.5 microgram in 0.2 microliter) into the ipsilateral, but not the contralateral, BLA 10 min prior to training blocked the hippocampal glucocorticoid effects on memory consolidation. Infusions of the muscarinic cholinergic antagonist atropine (0.5 microgram in 0.2 microliter) into either the ipsilateral or contralateral BLA before training did not block the hippocampal glucocorticoid effects. These findings provide further evidence that beta-adrenergic activity in the BLA is essential in enabling glucocorticoid-induced modulation of memory consolidation and are consistent with the hypothesis that the BLA regulates the strength of memory consolidation in other brain structures. The ipsilateral nature of the BLA-hippocampus interaction indicates that BLA influences on hippocampal memory processes are mediated through neural pathways rather than by influences by means of the activation of peripheral stress responses.

Deficit in selective and divided attention associated with cholinergic basal forebrain immunotoxic lesion produced by 192-saporin; motoric/sensory deficit associated with Purkinje cell immunotoxic lesion produced by OX7-saporin.

The immunotoxin 192-saporin, infused intracerebroventricularly into rats, destroys cholinergic neurons in the basal forebrain nuclei. Doses required for complete cholinergic loss also kill some Purkinje cells. The immunotoxin OX7-saporin, when infused intraventricularly into rats, destroys Purkinje cells in a pattern similar to that produced by 192-saporin, without affecting cholinergic neurons. Thus, we used OX7-saporin to distinguish behavioral effects of 192-saporin due to cerebellar damage versus those due to cholinergic cell loss. Three doses of 192-saporin (1.6, 2.6, and 3.3 micrograms/rat) were chosen along with a dose of OX7-saporin (2.0 micrograms/rat) that produced Purkinje loss equivalent to the two highest doses of 192-saporin. Groups of Fischer-344 rats were trained in the multiple choice reaction time task and retested with more complex tasks after lesioning. They were also tested in the water maze, passive avoidance, acoustic startle, and open field. The OX7-saporin group exhibited changes in many tests suggesting hypermotility and sensory deficits. The 192-saporin groups differed from the OX7-saporin group when they displayed deficits in multiple choice reaction time tasks in which novel challenges were introduced, including sessions with a noise distractor, shortened and lengthened intertrial intervals, and use of nine instead of five sources of light stimulus. The 192-saporin groups showed no impairment in the other tasks. The cholinergic basal forebrain lesion may mask some of the effects of cerebellar damage up to a threshold after which effects of Purkinje cell loss predominate when 192-saporin is administered intraventricularly.

Short-term and complete reversal of NGF effects in rats with lesions of the nucleus basalis magnocellularis.

Rats received bilateral quisqualic acid lesions of the nucleus basalis magnocellularis. Three weeks after lesioning, osmotic minipumps were implanted that released recombinant human nerve growth factor or cytochrome c at a dosage of 5.0 microg rat-1 day-1 through intracerebroventricular cannulas for 7 weeks. One quarter of the rats were sacrificed at the end of the treatment, while the rest of the animals were sacrificed 2, 8, and 12 weeks after termination of NGF/cc treatment. ICV administration of nerve growth factor (NGF) transiently reduced weight gain. NGF maximally increased choline acetyltransferase activity in all cortical regions, the olfactory bulb and the hippocampus between 20% and 56% at the end of the treatment. This increase linearly declined and completely regressed during the 12-week withdrawal period both in regions affected and unaffected by the lesion. Administration of NGF induced a short-lasting hypertrophy of low affinity NGF receptor immunoreactive neurons within the nucleus basalis magnocellularis (NBM), the horizontal limb of the diagonal band of Broca, and the medial septum. In contrast, QUIS-induced NBM lesions permanently reduced ChAT activity most pronounced in the frontal and parietal cortex up to 45%. Furthermore, QUIS induced a permanent loss of p75NGFr-immunoreactive neurons within the NBM and the DB without affecting the MS. These findings suggest that degenerating cholinergic neurons of the NBM and HDB do not spontaneously recover after lesioning and may require continuous neurotrophic support by NGF to ameliorate cholinergic hypofunctioning.