First 2-3 words of Title Norepinephrine Norepinephrine’s Role in Memory Bao Ngo Norwich University 1 First 2-3 words of Title 2 Introduction Norepinephrine (NE), also called noradrenaline is a neurotransmitter active in both the brain and the sympathetic nervous system. Its cell bodies are divided into two regions of the midbrain and brainstem, the locus coeruleus (LC) and the lateral tegmental area (Watson et al., 2012). Noradrenergic axons from these regions project mainly over the cerebrum, including the cerebral cortex, limbic system, and thalamic nuclei. Norepinephrine has a variety of actions including participating in alertness, mood, and memory. The LC is coupled with two primary moves of NE release; tonic and burst firing (Watson et al., 2012), and is associated with tonic control of wakefulness, and through tonic firing, NE effects sleep, attention, stress, inflammation, and many other processes (O’Donnell et al., 2012). This aids to integrate internal physiological demands with how external environmental inputs are gated, in addition to alter cortical responses both to slow changes in physiological function and critical moments of behavioral stimuli. In addition, Astrocytes are widely affected by NE. Astrocytes express primarily y α1, α2 and β1 adrenergic receptors and their activation have all been linked to robust downstream effects on the supportive functions of astrocytes (O’Donnell et al., 2012). NE enhances glutamate uptake, and increases production and breakdown of glycogen, showing that NE as a booster of the critical functions of astrocytes in anticipation of increased demand. The α1-adrenergic receptor upon activation improves glutamate re-uptake and optimizes temporal resolution and signal-to-noise ratio of glutamatergic transmission. While the primary function of α2-adrenergic receptors is to increase glycogenesis from glucose as part of the glycogen shunt during quiescent periods of neuronal activity. First 2-3 words of Title 3 Role in Memory Norepinephrine’s role in behavior is to flexibly adapt networks to enhance performance on whatever task is currently relevantly. For example, in higher-order processing areas, NE has been shown to alter network activity in attention and working memory (O’Donnell et al., 2012). Studies have shown that reduced cortical NE levels by application of the α2A-adrenergic receptor agonist clonidine to the LC reduces neuronal firing, while α1- adrenergic receptor activation caused a delayed increase in activity (O’Donnell et al., 2012). Another study showed that in rats, reduction of NE levels via clonidine injection into the LC decrease network activation and impaired attention, while a PET imaging study in humans using i.v clonidine enhanced frontoparietal connectivity when subjects were focused on a task. Activity was also reduced when subjects were resting with eyes closed, showing that NE plays an important role in modulating attention via the α2A-adrenergic receptor (O’Donnell et al., 2012). Norepinephrine has been shown to have a prominent role in memory consolidation and memory selection. In the mammalian brain, memory traditionally progresses through protein synthesis-independent that generally last a few hours (short-term) and is followed by a protein synthesis-dependent long-term memory. Short-term memory (STM) is associated with the ability to keep a small amount of information available for a short period of time and Long-term memory is associated with unlimited storage information to be maintained for long periods or even for life (Camina & Güell, 2017). Studies have shown that phases of memory consolidation points are critical to memory formation and have linked noradrenergic signaling. Works by Leif Hertz and Marie Gibbs has shown that these consolidation points are reliant on astrocytes. Injection of glycogen phosphorylase inhibitor DAB prevents learning when applied 5 minutes before, 25-35 and 60 minutes after learning. Also, α2-adrenergic antagonist application prevents First 2-3 words of Title 4 learning, specifically when applied at 10–20 or 40–50 min post-learning (O’Donnell et al., 2012). With further work, alternating patterns of activity correlate with the effects of adrenergic receptors on astrocyte metabolism. Furthermore, increased astrocyte glycogenolysis has been associated with its role in supporting increased glutamate and glutamine synthesis after learning (O’Donnell et al., 2012). Another study displayed that the glycogenolysis inhibitor DAB induced memory impairment at specific times after learning but can be recovered by astrocyte-specific metabolic substrate acetate with aspartate. Combined with glutamine, this provides evidence that astrocytic β-adrenergic receptor mediates glycogenolysis and in turn is a critical component of memory consolidation (O’Donnell et al., 2012). When NE concentrations become high enough to interact with β-adrenoreceptors, triggering protein synthesis processes that allow long-term memory consolidation of high-priority. In turn, lower NE concentrations at less active regions lead to short-term memory, ensuring less important events are forgotten or removed (Mathers et al., 2015). Selectivity in Perception and Memory Norepinephrine has been shown to be also associated with selective perception and memory. A study by Mather et al. proposes that under arousal, glutamate interaction with NE enhances high priority representations and out-compete or inhibit lower priority representations. Based on the arousal-biased competition (ABC) model, which proposes that stimuli must compete for limited mental resources (Mather et al., 2015), and the glutamate amplifies noradrenergic effects (GANE) model, that proposes arousal amplifies the activation difference between high- and low-priority representations from the locus coeruleus-norepinephrine system. Mather et al. describes that according to the GANE model, excitatory external responses like loud sounds or something exciting leads to a surge in NE release, which enhances activity of First 2-3 words of Title 5 neurons transmitting high-priority mental representations and inhibits activity of neurons transmitting lower-priority mental representations. People tend to prioritize emotional stimuli due to top-down goals like, increasing happiness and avoiding pain, emotional priority like, reward or punishment, and/or bottom-up priority, like a threat to well-being. Arousal can also either impair or enhance memory consolidation depending on priority. One study tested this by giving participants lists of objects one at a time, with a single visual oddball. One condition, in which participants were asked to recall the name of the oddball picture (I.e., an orange), the object before the oddball was of low priority. Another condition, participants were asked to recall the name of the object before the oddball, and that object was of high priority (Mathers et al., 2015). This shows the effects of arousal can either enhance or impair memory consolidation depending on memory. Another model called, the biased attention via norepinephrine (BANE) model, proposes that “affectively salient stimuli active the LC-NE system to optimize their own processes” (Mathers et al., 2015). While also, affect-biased attention is particular from both topdown and bottom-up visual attention. Emotional salience is detected by the amygdala and the orbitofrontal cortex, and the amygdala serves as a pathway between the LC-NE that further biases attention and memory for high priority information from NE release (Mathers et al., 2015). Conclusion Norepinephrine is a neurotransmitter with a wide range of effects on memory and many more processes. Under arousal, NE can be associated with memory consolidation, as it can either impair or enhance it. NE’s effects of astrocytes and glutamate play a large role in long-term memory and short-term memory, as concentrations of NE release can determine either or. First 2-3 words of Title 6 References Camina, E., & Güell, F. (2017). The neuroanatomical, neurophysiological and psychological basis of memory: Current models and their origins. Frontiers in Pharmacology, 8. https://doi.org/10.3389/fphar.2017.00438 Mather, M., Clewett, D., Sakaki, M., & Harley, C. W. (2015). Norepinephrine ignites local hotspots of neuronal excitation: How arousal amplifies selectivity in perception and memory. Behavioral and Brain Sciences, 39. https://doi.org/10.1017/s0140525x15000667 O'Donnell, J., Zeppenfeld, D., McConnell, E., Pena, S., & Nedergaard, M. (2012). Norepinephrine: a neuromodulator that boosts the function of multiple cell types to optimize CNS performance. Neurochemical research, 37(11), 2496–2512. https://doi.org/10.1007/s11064012-0818-x Watson, N. V., & Breedlove, S. M. (2012). The mind's machine: Foundations of brain and behavior. Sunderland, Mass: Sinauer Associates.
