Gary Aston-Jones
Director, Brain Health Institute & Murray and Charlotte Strongwater Endowed Chair in Neuroscience and Brain Health. Rutgers University, Piscataway. USA
November 30
3:00pm-6:00pm Central European Time
December 1
3:00pm-6:00pm Central European Time
Regulated motivation is critical to adaptive behavior, and many behavioral disorders can be seen as motivational dysregulation. Motivation not only regulates ongoing behavior, but also attention/salience, learning and memory because attention and reward-based learning are driven by behavior that in turn is linked to motivational goals. Disorders of motivation are most readily associated with drug and alcohol addiction, but also correspond to eating disorders, gambling problems, and a range of other compulsive disorders, including attentional and learning problems. Therefore, therapies that target motivational systems have a broad range of potential therapeutic applications. Ventral midbrain dopamine (VTA-DA) neurons comprise a key brain system linked with motivation for many rewards (both consummatory and non-consummatory, e.g., sex).
Circuits and mechanisms that regulate activity of VTA-DA neurons are critical for motivation in relation to reward availability, behavioral utility and expected outcome. The hypothalamic neuropeptide system of orexin/hypocretin neurons is critically involved in arousal as well as in motivation for many rewards, including a wide range of drugs of abuse and alcohol, food (including non-caloric saccharin) and sex; this motivational regulation involves at least in part orexin innervation of VTA.
Other brain stem nuclei important for these functions include the noradrenergic locus coeruleus (LC) system, which is a major input to VTA and has long been implicated in arousal, attention and salience attribution. The LC is the largest source of noradrenaline/norepinephrine (NE) in the brain. LC efferent projections extend broadly through the brain and spinal cord, and exert a multitude of cellular actions, including modulation of responses of target neurons to their other inputs. We will review such basic data, and show how the LC system plays roles in multiple dimensions of behavior, including in arousal and sleep-wake control, attention, behavioral flexibility and decision outcome. These various functions are encapsulated in the Adaptive Gain Theory, a framework that uses computational modeling approaches to understand network-wide actions of LC in brain and behavior. Inputs to LC will also be reviewed, including evidence for regulation by areas across multiple levels of the neuraxis, with differential innervation of the LC nuclear core vs dendritic shell. One particularly intriguing and strong input is from orexin/hypocretin neurons, located in dorsomedial, perifornical and lateral hypothalamus. Like LC, orexin neurons play a major role in regulation of arousal and the sleep-wake cycle. Studies over the last 15 years have also found that this system functions in reward processing, including in addiction to a variety of drugs. We will review studies finding that orexin neurons are strongly activated by conditioned stimuli (CSs) associated with salient rewards, and in turn increase the responsiveness of midbrain dopamine neurons to glutamate inputs associated with such CSs. This is thought to activate motivational systems and behavioral responsiveness. The strong orexin input to LC neurons depolarizes these cells and decreases their potassium conductance to further increase their excitability. Thus, activation of orexin neurons links motivational activation (via modulation of dopamine neurons) to adaptive gain and decision outcome (via projections to LC). We will discuss how this interaction might direct motivational activation towards specific behaviors in response to salient stimuli.
The LC system has been implicated in a variety of neuropsychiatric disorders, including depression, ADHD, stress disorders and neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Its location in deep brain stem has made it difficult to extrinsically manipulate activity of LC neurons. We will review experiments that reveal a circuit connection from the suprachiasmatic nucleus (SCN) to LC, with a relay in dorsomedial hypothalamus. Not only does this provide a circuit mechanism for circadian regulation of arousal, but also affords a novel avenue for extrinsic regulation of LC activity. We will discuss very recent experiments that use chemogenetics (DREADDs) to activate retinal ganglion cell inputs to SCN, and in turn activate the SCN-to-LC circuit; we term this the Photic Regulation of Arousal and Mood (PRAM) pathway. Results indicate that manipulation of the PRAM pathway is a relatively non-invasive method for regulating LC activity, in part via orexin inputs from hypothalamus, and that this has beneficial effects on depression in animal models.