Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory

Abstract

Dopamine neurotransmission in the dorsal hippocampus is critical for a range of functions from spatial learning and synaptic plasticity to the deficits underlying psychiatric disorders such as attentiondeficit hyperactivity disorder. The ventral tegmental area (VTA) is the presumed source of dopamine in the dorsal hippocampus. However, there is a surprising scarcity of VTA dopamine axons in the dorsal hippocampus despite the dense network of dopamine receptors. We have explored this apparent paradox using optogenetic, biochemical, and behavioral approaches and found that dopaminergic axons and subsequent dopamine release in the dorsal hippocampus originate from neurons of the locus coeruleus (LC). Photostimulation of LC axons produced an increase in dopamine release in the dorsal hippocampus as revealed by high-performance liquid chromatography. Furthermore, optogenetically induced release of dopamine from the LC into the dorsal hippocampus enhanced selective attention and spatial object recognition via the dopamine D1/D5 receptor. These results suggest that spatial learning and memory are energized by the release of dopamine in the dorsal hippocampus from noradrenergic neurons of the LC. The present findings are critical for identifying the neural circuits that enable proper attention selection and successful learning and memory.dopamine | locus coeruleus | hippocampus | memory | attention D opamine is a neurotransmitter released throughout the brain to encode salience and facilitate the formation of associative memory (1, 2). When released into the dorsal hippocampus, dopamine binds to D1/D5 receptors to promote attention, episodic memory formation, spatial learning, and synaptic plasticity (3-5). Successful spatial learning requires that hippocampal place cells, location-encoding pyramidal neurons (6), display consistent and stable patterns of neural activity, a process that can be enhanced by selective attention to spatial cues and by dopamine agonists (7,8). Conversely, dopamine receptor blockade attenuates the ability of spatial attention to stabilize the firing pattern of hippocampal place cells (8). The role of dopamine in driving attentional processes is highlighted by the fact that methylphenidate, one of the most common treatments for attention-deficit hyperactivity disorder (ADHD), improves attention by increasing synaptic availability of dopamine in the hippocampus, as well as in the prefrontal cortex and striatum (9-11). These findings suggest that dopamine is critical for the selective attention underlying spatial learning and memory.For decades, the ventral tegmental area (VTA) has been the presumed source of hippocampal dopamine. However, in recent years, the source of dopamine in the dorsal hippocampus has become less clear. McNamara et al. (12) argued that a dopaminergic projection from the VTA to the dorsal hippocampus promoted hippocampal reactivation during sleep and stabilized memory. However, only 10% of the sparse projection from the VTA to the hippocampus contains dopamine, raising the...

Locus coeruleus input to hippocampal CA3 drives single-trial learning of a novel context

“…S3). It is widely accepted that the LC is the major source of norepinephrine, and although we cannot rule out the existence of an indirect source of dopamine, recent studies support the hypothesis that the LC could release dopamine, alongside norepinephrine, in the hippocampus (8,12,16,33). Our data are consistent with previous studies showing that the dopaminergic neuromodulatory system enhances the encoding of novel information by modulating hippocampal synaptic strength (14,34,35).…”

“…S3B). These results demonstrate the release of dopamine elicited by the activation of LC neurons under physiological conditions, as supported by recent gain-of-function stimulation studies (8,12), and reveal the importance of LC projections to hippocampal CA3 in single-trial learning.…”

“…While previous studies have shown LC projections to the hippocampus (12,18), comparative analysis of LC fibers between hippocampal subregions have not yet been reported. Strong expression of enhanced yellow fluorescent protein (EYFP) in LC-specific Cre mice with double-floxed inverted orientation (DIO) virus enabled us to observe small fibers and to quantify relative fluorescence in each hippocampal subregion (Fig.…”

“…Another source of neuromodulation in the hippocampus is the ventral tegmental area (VTA), which also responds to novelty. However, studies have shown that VTA projections to dorsal hippocampus are scarce, whereas LC projections are abundant (8,12,13). In addition, dopamine, which is the most prominently implicated neuromodulator in novelty signaling (14), was demonstrated to be released from the LC, along with norepinephrine in the cortex (15) and in the hippocampus (8,12,16).…”

Neurochemicals, Behaviours and Psychiatric Perspectives of Neurological Diseases

“…Several disruptions in the dopaminergic (DAergic) system have been reported in AD. Reduced dopamine levels were found in the cingulate gyrus, nucleus amygdalae, nucleus caudatus, putamen, raphae, and substantia nigra in patients [165]. The reduced levels of dopamine receptors, especially the D2 subtype are associated with the pathology of AD [17].…”