Abstract
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.
Highlights
The locus coeruleus (LC) has long been implicated in learning and memory and has recently been highlighted as a possible ground zero for Alzheimer’s Disease, a memory pathway selective disease (Braak et al, 2011; Braak and Del Tredici, 2015)
The left hemisphere LC was counted in three central sections to estimate co-localization
Co-localization was assessed in 20 rats and ChR2 channels were observed in more than 70% of the DBH neurons. These numerical data are consistent with earlier optogenetic images for rats, in which an overshadowing of DBH staining by ChR2-EYFP is occasionally observed (Hickey et al, 2014; Takeuchi et al, 2016)
Summary
The locus coeruleus (LC) has long been implicated in learning and memory and has recently been highlighted as a possible ground zero for Alzheimer’s Disease, a memory pathway selective disease (Braak et al, 2011; Braak and Del Tredici, 2015). NE-long term potentiation (NE-LTP) of perforant path (PP) input has been repeatedly demonstrated in vitro (Lacaille and Harley, 1985; Stanton and Sarvey, 1985, 1987) and in vivo (Neuman and Harley, 1983; Harley and Milway, 1986; Harley et al, 1989; Walling and Harley, 2004) in this structure and, more recently, NE-long term depression (NE-LTD; Hansen and Manahan-Vaughan, 2015b) has been reported. Later experiments demonstrated that glutamatergic (Walling and Harley, 2004) and orexinergic activation of the LC (Walling et al, 2004), evoking natural release of NE in DG, produces both transient and long-lasting PP-spike potentiation that is β-adrenergicdependent. While most in vivo experiments were conducted under urethane-anesthesia, the same pattern of results is seen with glutamatergic LC activation in awake rats and NE-spike potentiation can last up to 24 h (Walling et al, 2004)
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