Norepinephrine, acting through ␤-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 ␤-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 shortterm 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.

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 (ϳ1-2 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 (ϳ1-2 min). ␤-␥ 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.

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 β1-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. Electronic supplementary material The online version of this article (10.1186/s13195-019-0511-2) contains supplementary material, which is available to authorized users.

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 pilocarpineinduced 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.