Evidence that ovarian hormones, but not diet and exercise, contribute to the sex disparity in post-traumatic stress disorder.

Females are twice as likely as males to receive a diagnosis of post-traumatic stress disorder (PTSD). One hypothesis for this sex disparity is that ovarian hormones, including estrogen and progesterone, contribute to PTSD risk. Alternatively, sex differences in lifestyle factors, such as diet and exercise, may play a role in PTSD risk. Using data from the Atlantic Partnership for Tomorrow's Health (PATH) cohort (n = 16,899), the relationship between endogenous hormone fluctuations (e.g., menarche, pregnancy, and menopause), exogenous hormone use (e.g., hormonal contraception and hormone replacement therapy (HRT)) and lifestyle variables (diet and exercise habits, as measured by the Mediterranean Diet Adherence Screener, Healthy Eating Index, and International Physical Activity Questionnaire) with PTSD diagnosis and treatment were analyzed. While several hormonal variables, including contraceptive use, higher total number of pregnancies, younger menarche age, and having undergone menopause increased the risk of PTSD, no lifestyle variables contributed to an increased risk of PTSD diagnosis. These findings support the theory that ovarian hormones contribute to the sex-linked disparity in PTSD diagnosis.

Sprague-Dawley Rats Differ in Responses to Medial Perforant Path Paired Pulse and Tetanic Activation as a Function of Sex and Age.

Network plasticity in the medial perforant path (MPP) of adult (five to nine months) and aged (18-20 months) urethane-anesthetized male and female Sprague Dawley rats was characterized. Paired pulses probed recurrent networks before and after a moderate tetanic protocol. Adult females exhibited greater EPSP-spike coupling suggesting greater intrinsic excitability than adult males. Aged rats did not differ in EPSP-spike coupling but aged females had larger spikes at high currents than males. Paired pulses suggested lower GABA-B inhibition in females. Absolute population spike (PS) measures were larger post-tetani in female rats than male rats. Relative population spike increases were greatest in adult males relative to females and to aged males. EPSP slope potentiation was detected with normalization in some post-tetanic intervals for all groups except aged males. Tetani shortened spike latency across groups. Tetani-associated NMDA-mediated burst depolarizations were larger for the first two trains in each tetanus in adult males than other groups. EPSP slopes over 30 min post-tetani predicted spike size in female rats but not in males. Replicating newer evidence MPP plasticity in adult males was mediated by increased intrinsic excitability. Female MPP plasticity was related to synaptic drive increases, not excitability increases. Aged male rats were deficient in MPP plasticity.

The 'a, b, c's of pretangle tau and their relation to aging and the risk of Alzheimer's Disease.

Braak has described the beginnings of Alzheimer's Disease as occurring in the locus coeruleus. Here we review these pretangle stages and relate their expression to recently described normal features of tau biology. We suggest pretangle tau depends on characteristics of locus coeruleus operation that promote tau condensates. We examine the timeline of pretangle and tangle appearance in locus coeruleus. We find catastrophic loss of locus coeruleus neurons is a late event. The strong relationship between locus coeruleus neuron number and human cognition underscores the utility of a focus on locus coeruleus. Promoting locus coeruleus health will benefit normal aging as well as aid in the prevention of dementia. Two animal models offering experimental approaches to understanding the functional change initiated by pretangles in locus coeruleus neurons are discussed.

An experimental model of Braak's pretangle proposal for the origin of Alzheimer's disease: the role of locus coeruleus in early symptom development.

BACKGROUND: The earliest brain pathology related to Alzheimer's disease (AD) is hyperphosphorylated soluble tau in the noradrenergic locus coeruleus (LC) neurons. Braak characterizes five pretangle tau stages preceding AD tangles. Pretangles begin in young humans and persist in the LC while spreading from there to other neuromodulatory neurons and, later, to the cortex. While LC pretangles appear in all by age 40, they do not necessarily result in AD prior to death. However, with age and pretangle spread, more individuals progress to AD stages. LC neurons are lost late, at Braak stages III-IV, when memory deficits appear. It is not clear if LC hyperphosphorylated tau generates the pathology and cognitive changes associated with preclinical AD. We use a rat model expressing pseudohyperphosphorylated human tau in LC to investigate the hypothesis that LC pretangles generate preclinical Alzheimer pathology. METHODS: We infused an adeno-associated viral vector carrying a human tau gene pseudophosphorylated at 14 sites common in LC pretangles into 2-3- or 14-16-month TH-Cre rats. We used odor discrimination to probe LC dysfunction, and we evaluated LC cell and fiber loss. RESULTS: Abnormal human tau was expressed in LC and exhibited somatodendritic mislocalization. In rats infused at 2-3 months old, 4 months post-infusion abnormal LC tau had transferred to the serotonergic raphe neurons. After 7 months, difficult similar odor discrimination learning was impaired. Impairment was associated with reduced LC axonal density in the olfactory cortex and upregulated ß1-adrenoceptors. LC infusions in 14-16-month-old rats resulted in more severe outcomes. By 5-6 months post-infusion, rats were impaired even in simple odor discrimination learning. LC neuron number was reduced. Human tau appeared in the microglia and cortical neurons. CONCLUSIONS: Our animal model suggests, for the first time, that Braak's hypothesis that human AD originates with pretangle stages is plausible. LC pretangle progression here generates both preclinical AD pathological changes and cognitive decline. The odor discrimination deficits are similar to human odor identification deficits seen with aging and preclinical AD. When initiated in aged rats, pretangle stages progress rapidly and cause LC cell loss. These age-related outcomes are associated with a severe learning impairment consistent with memory decline in Braak stages III-IV.

Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment.

Locus coeruleus (LC) neurons, the source of hippocampal norepinephrine (NE), are activated by novelty and changes in environmental contingencies. Based on the role of monoamines in reconfiguring invertebrate networks, and data from mammalian systems, a network reset hypothesis for the effects of LC activation has been proposed. We used the cellular compartmental analysis of temporal FISH technique based on the cellular distribution of immediate early genes to examine the effect of LC activation and inactivation, on regional hippocampal maps in male rats, when LC activity was manipulated just before placement in a second familiar (A/A) and/or novel environment (A/B). We found that bilateral phasic, but not tonic, activation of LC reset hippocampal maps in the A/A condition, whereas silencing the LC with clonidine before placement in the A/B condition blocked map reset and a familiar map emerged in the dentate gyrus, proximal and distal CA1, and CA3c. However, CA3a and CA3b encoded the novel environment. These results support a role for phasic LC responses in generating novel hippocampal sequences during memory encoding and, potentially, memory updating. The silencing experiments suggest that novel environments may not be recognized as different by dentate gyrus and CA1 without LC input. The functional distinction between phasic and tonic LC activity argues that these parameters are critical for determining network changes. These data are consistent with the hippocampus activating internal network representations to encode novel experiential episodes and suggest LC input is critical for this role.SIGNIFICANCE STATEMENT Burst activation of the broadly projecting novelty signaling system of the locus coeruleus initiates new network representations throughout the hippocampus despite unchanged external environments. Tonic activation does not alter network representations in the same condition. This suggests differences in the temporal parameters of neuromodulator network activation are critical for neuromodulator function. Silencing this novelty signaling system prevented the appearance of new network representations in a novel environment. Instead, familiar representations were expressed in a subset of hippocampal areas, with another subset encoding the novel environment. This "being in two places at once" argues for independent functional regions within the hippocampus. These experiments strengthen the view that internal states are major determinants of the brain's construction of environmental representations.

Locus Coeruleus Optogenetic Light Activation Induces Long-Term Potentiation of Perforant Path Population Spike Amplitude in Rat Dentate Gyrus.

Norepinephrine (NE) in dentate gyrus (DG) produces NE-dependent long-term potentiation (NE-LTP) of the perforant path-evoked potential population spike both in vitro and in vivo. Chemical activators infused near locus coeruleus (LC), the source of DG NE, produce a NE-LTP that is associative, i.e., requires concurrent pairing with perforant path (PP) input. Here, we ask if LC optogenetic stimulation that allows us to activate only LC neurons can induce NE-LTP in DG. We use an adeno-associated viral vector containing a depolarizing channel (AAV8-Ef1a-DIO-eChR2(h134r)-EYFP-WPRE) infused stereotaxically into the LC of TH:Cre rats to produce light-sensitive LC neurons. A co-localization of ~62% in LC neurons was observed for these channels. Under urethane anesthesia, we demonstrated that 5-10 s 10 Hz trains of 30 ms light pulses in LC reliably activated neurons near an LC optoprobe. Ten minutes of the same train paired with 0.1 Hz PP electrical stimulation produced a delayed NE-LTP of population spike amplitude, but not EPSP slope. A leftward shift in the population spike input/output curve at the end of the experiment was also consistent with long-term population spike potentiation. LC neuron activity during the 10 min light train was unexpectedly transient. Increased LC neuronal firing was seen only for the first 2 min of the light train. NE-LTP was more delayed and less robust than reported with LC chemo-activation. Previous estimates of LC axonal conduction times suggest acute release of NE occurs 40-70 ms after an LC neuron action potential. We used single LC light pulses to examine acute effects of NE release and found potentiated population spike amplitude when a light pulse in LC occurred 40-50 ms, but not 20-30 ms, prior to a PP pulse, consistent with conduction estimates. These effects of LC optogenetic activation reinforce evidence for a continuum of NE potentiation effects in DG. The single pulse effects mirror an earlier report using LC electrical stimulation. These acute effects support an attentional role of LC activation. The LTP of PP responses induced by optogenetic LC activation is consistent with the role of LC in long-term learning and memory.

The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this impairment was largely reversed at 24-h. Animals in the high-dose NTP (20mg/kg/day) group were impaired at both short- and long-term intervals. Activity levels, used as an index of location memory during the ORT, demonstrated that rats receiving DMI were again impaired at retaining memory for location. DMI dose-dependently disrupts LTP in the dentate gyrus of anesthetized rats and also disrupts memory for tests of spatial memory when administered for long periods.

Modulation of the perforant path-evoked potential in dentate gyrus as a function of intrahippocampal ß-adrenoceptor agonist concentration in urethane-anesthetized rat.

BACKGROUND: ß-adrenoceptor activation in the hippocampus is sufficient to induce heterosynaptic long-term potentiation of perforant path input to the dentate gyrus. However, in vitro and in vivo studies suggest the plasticity effects of ß-adrenoceptor activation may vary depending on the level of receptor activation. METHODS: The present experiments use an in vivo model concurrently infusing differing concentrations of the ß-adrenoceptor agonist, isoproterenol (ISO; 0, 0.1, 1, 10, and 100 µmol/L in aCSF; 1 µL over 12.5 min) in the dentate gyrus, while monitoring changes in the perforant path-evoked potential at the same site. RESULTS: Long-term depression (LTD) of fEPSP slope was elicited by 0.1 µmol/L ISO. Higher doses did not alter fEPSP slope. Maximal long-term potentiation of the perforant path-evoked population spike (183% >3 h) occurred at 10 µmol/L ISO. Transient depression of spike amplitude occurred at 0.1 µmol/L ISO. CONCLUSIONS: These data demonstrate concentration-dependent effects of ß-adrenoceptor activation on the perforant path-evoked potential. Long-term depression and long-term potentiation of perforant path-evoked responses are variably elicited as a function of the degree of receptor activation.

Selective wheat germ agglutinin (WGA) uptake in the hippocampus from the locus coeruleus of dopamine-ß-hydroxylase-WGA transgenic mice.

We generated transgenic mice in which a trans-synaptic tracer, wheat germ agglutinin (WGA), was specifically expressed in the locus coeruleus (LC) neurons under the control of the dopamine-ß-hydroxylase (DBH) gene promoter. WGA protein was produced in more than 95% of the tyrosine hydroxylase (TH)-positive LC neurons sampled. Transynaptic transfer of WGA was most evident in CA3 neurons of the hippocampus, but appeared absent in CA1 neurons. Faint but significant WGA immunoreactivity was observed surrounding the nuclei of dentate granule cells. Putative hilar mossy cells, identified by the presence of calretinin in the ventral hippocampus, appeared uniformly positive for transynaptically transferred WGA protein. GAD67-positive interneurons in the hilar and CA3 regions tended to be WGA-positive, although a subset of them did not show WGA co-localization. The same mixed WGA uptake profile was apparent when examining co-localization with parvalbumin. The selective uptake of WGA by dentate granule cells, mossy cells, and CA3 pyramidal neurons is consistent with evidence for a large proportion of conventional synapses adjacent to LC axonal varicosities in these regions. The lack of WGA uptake in the CA1 region and its relatively sparse innervation by DBH-positive fibers suggest that a majority of the TH-positive classical synapses revealed by electron microscopy in that region may be producing dopamine. The overall pattern of WGA uptake in these transgenic mice implies a selective role for the granule cell-mossy cell-CA3 network in processing novelty or the salient environmental contingency changes signaled by LC activity.

Selective tuning of hippocampal oscillations by phasic locus coeruleus activation in awake male rats.

Theta and gamma oscillations are thought to provide signal sets that promote neural coding of cognitive processes. Over 40 yrs ago, Jeffrey Gray reported event-related changes in a narrow band of hippocampal theta (7.5-8.5 Hz) which appeared to involve norepinephrine (NE) release from, the noradrenergic nucleus, the locus coeruleus (LC). These event-related alterations in EEG were elicited by novelty, attentional changes, the use of preparatory signals, and signal-mismatch events. Gray et al. have since provided indirect evidence that supports the role of NE in the modulation of 7.5- to 8.5-Hz oscillations in the hippocampus, but studies investigating the effects of direct LC activation in awake rats have been lacking. In the present study, dentate gyrus EEG was examined during glutamatergic activation of the LC in awake male rats in relation to plasticity effects on simultaneously recorded perforant path-evoked field potentials. Glutamate-injected animals were divided into three groups based on histological and plasticity outcomes; perforant path stimulated controls were also included. The three injected groups were: (1) rats with positive LC placements, demonstrating NE-LTP of the dentate gyrus evoked potential, (2) rats with positive LC placements, without NE-LTP, and (3) Non-LC injected controls. Activation of the LC in awake rats demonstrating NE-LTP increased the relative power of 7- to 9-Hz theta, a result masked in broader 4- to 12-Hz analysis. Comparatively, urethane-anesthetized rats showed an increase in 5-7 Hz, but not 7- to 9-Hz theta with LC activation. Discriminative analysis in the approximate theta band predicted by Gray (7.4-8.5 Hz) revealed that awake rats demonstrating NE-LTP had increased relative power in this narrow frequency compared to rats receiving perforant path only (noninjected) and Non-LC injected rats. Transiently reduced gamma (20-40 Hz) relative power was most commonly observed in rats with verified LC placements failing to express NE-LTP. Given current theories of LC function, these results suggest oscillatory tuning within the theta and gamma range may facilitate shifts in cognitive set.

Acute and chronic changes in glycogen phosphorylase in hippocampus and entorhinal cortex after status epilepticus in the adult male rat.

Glial cells provide energy substrates to neurons, in part from glycogen metabolism, which is influenced by glycogen phosphorylase (GP). To gain insight into the potential subfield and laminar-specific expression of GP, histochemistry can be used to evaluate active GP (GPa) or totalGP (GPa + GPb). Using this approach, we tested the hypothesis that changes in GP would occur under pathological conditions that are associated with increased energy demand, i.e. severe seizures (status epilepticus or 'status'). We also hypothesized that GP histochemistry would provide insight into changes in the days and weeks after status, particularly in the hippocampus and entorhinal cortex, where there are robust changes in structure and function. One hour after the onset of pilocarpine-induced status, GPa staining was reduced in most regions of the hippocampus and entorhinal cortex relative to saline-injected controls. One week after status, there was increased GPa and totalGP, especially in the inner molecular layer, where synaptic reorganization of granule cell mossy fibre axons occurs (mossy fibre sprouting). In addition, patches of dense GP reactivity were evident in many areas. One month after status, levels of GPa and totalGP remained elevated in some areas, suggesting an ongoing role of GP or other aspects of glycogen metabolism, possibly due to the evolution of intermittent, recurrent seizures at approximately 3-4 weeks after status. Taken together, the results suggest that GP is dynamically regulated during and after status in the adult rat, and may have an important role in the pilocarpine model of epilepsy.

Glycogen phosphorylase reactivity in the entorhinal complex in familiar and novel environments: evidence for labile glycogenolytic modules in the rat.

Active and total glycogen phosphorylase were measured histochemically in the entorhinal complex of male Sprague-Dawley rats. Rats were sacrificed from their home cage, or after 5 min in a novel holeboard. Hemispheres from each group were paired, sectioned and processed together. Glycogen phosphorylase reactivity highlighted entorhinal cortex in contrast to less densely stained perirhinal cortex or neocortex. The presubiculum, but not parasubiculum, was strongly reactive for glycogen phosphorylase. Within medial and lateral entorhinal cortex, modularity of active glycogen phosphorylase reactivity was apparent. In inner Layer I there were small ( approximately 50 microm) intense patches of active glycogen phosphorylase. In Layer III there were both small and larger ( approximately 200 microm), patches of active glycogen phosphorylase. Lamina dessicans was reactive. Layers V and VI were relatively unreactive. Exposure to a holeboard intensified the small patches of active glycogen phosphorylase in inner Layer I, while attenuating active glycogen phosphorylase reactivity in Layer III. Total glycogen phosphorylase was unaffected by exposure to the novel environment and exhibited a pattern of continuous dense reactivity suggesting enzyme reserves, particularly in superficial layers of entorhinal cortex. These patterns confirm earlier evidence that glycogenolytic demand in Layers I and III of rat entorhinal cortex is organized in a modular fashion and show that such demand can be modified by brief exposure to a novel holeboard.

Seizure susceptibility in intact and ovariectomized female rats treated with the convulsant pilocarpine.

Despite numerous neuroendocrinological studies of seizures, the influence of estrogen and progesterone on seizures and epilepsy remains unclear. This may be due to the fact that previous studies have not systematically compared distinct endocrine conditions and included all relevant controls. The goal of the present study was to conduct such a study using pilocarpine as chemoconvulsant. Thus, age and weight-matched, intact or ovariectomized rats were tested to determine incidence of status epilepticus and to study events leading to status. Intact female rats were sampled at each cycle stage (proestrus, estrus, metestrus, or diestrus 2). Convulsant was administered at the same time of day, 10:00-10:30 a.m. Statistical analysis showed that there was a significantly lower incidence of status on the morning of estrus, but differences were attenuated in older animals. Ovariectomized rats were distinct in their rapid progression to status. These results show that the incidence of status in female rats following pilocarpine injection, and the progression to pilocarpine-induced status, are influenced by reproductive state as well as age. The hormonal milieu present specifically on the morning of estrus appears to decrease susceptibility to pilocarpine-induced status, particularly at young ages. In contrast, the chronic absence of reproductive steroids that characterizes the ovariectomized rat leads to a more rapid progression to status. This dissociation between incidence vs. progression provides new insight into the influence of estrogen and progesterone on seizures.

Locus ceruleus activation suppresses feedforward interneurons and reduces beta-gamma electroencephalogram frequencies while it enhances theta frequencies in rat dentate gyrus.

The locus ceruleus is activated by novel stimuli, and its activation promotes learning and memory. Phasic activation of locus ceruleus neurons by glutamate enhances the dentate gyrus population spike amplitude and results in long-term potentiation of synaptic responses recorded after 24 h. Cholinergic activation of locus ceruleus neurons increases hippocampal . At the level of the cellular network, it is not clear how the potentiating effects of norepinephrine are mediated. Previous studies show that exogenous norepinephrine enhances inhibitory interneuron firing in the dentate gyrus. This finding appears at odds with evidence for potentiation. In this study, natural release of norepinephrine was induced by glutamate activation of locus ceruleus while we recorded EEGs and physiologically identified interneurons in the dentate gyrus of urethane-anesthetized rats. Feedforward neurons were inhibited (approximately 1-2 min) by locus ceruleus activation. Feedback interneurons showed both increased and decreased activity, whereas granule cells increased firing as predicted by evoked potential studies. EEG results replicated an increase in power (4-8 Hz) with locus ceruleus activation, but the effect with glutamatergic locus ceruleus activation was transient (approximately 1-2 min). Beta-gamma Frequencies were also transiently suppressed. Together, the data suggest that locus ceruleus activation enhances the throughput of concomitant sensory input by reducing feedforward inhibitory interneuron activity, which may reduce "binding" in existing cell assemblies, and enhances the conditions for synaptic plasticity through disinhibition, promotion of 4-8 Hz , and noradrenergic potentiation to facilitate the building of new representations.

Orexin-A infusion in the locus ceruleus triggers norepinephrine (NE) release and NE-induced long-term potentiation in the dentate gyrus.

The orexins (ORX-A/ORX-B) are neuroactive peptides known to have roles in feeding and sleep. Evidence of dense, excitatory projections of ORX-A neurons to the noradrenergic pontine nucleus, the locus ceruleus (LC), suggests ORX-A also participates in attention and memory. Activation of LC neurons by glutamate produces a beta-adrenergic receptor-mediated long-term potentiation (LTP) of the perforant path-evoked potential in the dentate gyrus, a target structure of the LC that has been implicated in memory. We asked whether ORX-A also activates norepinephrine (NE)-induced LTP by initiating NE release in the hippocampus. Here, we show that ORX-A infusion (0.25-25 fmol) into the LC produces a robust, beta-adrenergic receptor-dependent, long-lasting potentiation of the perforant path-evoked dentate gyrus population spike in the anesthetized rat. Pharmacological inactivation of the LC with an alpha2-adrenergic receptor agonist, before ORX-A infusion, prevents this potentiation. Analysis of NE concentrations in the hippocampus after ORX-A infusion into the LC reveals a transient, but robust, increase in NE release. Thus, this study demonstrates that the dense orexinergic projection to the LC promotes the induction of NE-LTP in the dentate gyrus. ORX-A modulation of LC activity may provide important support for the cognitive processes of attention and memory.

Locus ceruleus activation initiates delayed synaptic potentiation of perforant path input to the dentate gyrus in awake rats: a novel beta-adrenergic- and protein synthesis-dependent mammalian plasticity mechanism.

Norepinephrine, acting through beta-adrenergic receptors, is implicated in mammalian memory. In in vitro and in vivo studies, norepinephrine produces potentiation of the perforant path-dentate gyrus evoked potential; however, the duration and dynamics of norepinephrine-induced potentiation have not been explored over extended time periods. To characterize the long-term effects of norepinephrine on granule cell plasticity, the present study uses glutamatergic activation of the locus ceruleus (LC) to induce release of norepinephrine in the hippocampus of the awake rat and examines the subsequent modulation of the dentate gyrus evoked potential for 3 hr (short term) and 24 hr (long term) after LC activation. LC activation initiates a potentiation of the field EPSP slope observed 24 hr later. This late-phase potentiation of the synaptic potential is not preceded by early phase potentiation, although spike potentiation can be seen both immediately after, and 24 hr after, LC activation. Intracerebroventricular infusion of the beta-adrenergic antagonist, propranolol, or the protein synthesis inhibitor, anisomycin, before LC activation blocks the potentiation of perforant path input observed at 24 hr. The initiation of late-phase synaptic potentiation observed at 24 hr but not at the 3 hr after LC activation parallels the observation of a cAMP- and protein synthesis-dependent long-lasting synaptic facilitation in Aplysia that is not preceded by short-term synaptic facilitation. Locus ceruleus-initiated synaptic potentiation may selectively support long-term, rather than short-term, memory. The observation of selective initiation of long-term synaptic facilitation in a mammalian brain, as in invertebrates, is additional evidence that these two forms of memory depend on separable biological mechanisms.