The alert mode is generally triggered by strong surprise, which has both single neuron and system effects. At the single neuron level, expectation means that the cell is excited to some extent. Conversely, surprise means that the cell is hyperpolarized for some time. In many neuron types, when a hyperpolarized neuron suddenly receives enough inputs to get activated, its output is generally amplified to be stronger than that of activated partially excited neurons, showing a high frequency burst of action potentials. For example, after having been hyperpolarized for more than 100ms, thalamic neurons enter burst mode due to T-type Ca2+ channels causing a low-threshold spike, on top of which can ride a series of
high frequency APs [Sherman and Guillery, 2013, Cheong and Shin, 2013].
At the system level, expectation is manifested by the molding of neuronal terrain to channel incoming flow to a response. This is done via excitation of the channeling path, possibly coupled with inhibition along the path’s boundary. Surprise-induced flow is not restricted in this way, and can rapidly propagate in the alert and DM networks in neighbor- ing and far-away nodes. The strong burst firing of sensory and alert neurons induced by the surprise may be strong enough to activate their node’s execution neurons. Thus, surprises can generate strong high frequency activity in all networks, including the execution net- works. Moreover, since response neurons throughout cortex project to DA nuclei, surprises yield a burst of DA release (see below).
The role of valence. Small surprises occur continuously during wakefulness and usually do not trigger an alert mode (see OOA above). There are two typical cases in which an alert mode occurs: execution of a valenced or OOA innate (e.g., pain, quick external move- ment, food)48, or the unexpected occurrence of an event (usually appearance of an object) associated with such an innate. Note that these include positive innates, e.g., when seeing a sexually attractive person or even a friend (see skin response below). The amygdala is a key mediator of alert urgency in both cases, through CeA (in both cases) and BLA (in the latter case). As noted above, CeA projects to Rgen nuclei and the HT, BLA projects very strongly onto cortex, and the thalamus conveys direct sensory inputs to mPFC49. Thus, valence areas receive strong alert flow.
The alert mode is assisted by NE, AVP, CRH, SP and histamine. It has both brain and autonomic effects, the latter being quite similar to the initiation of classic stress response.
Norepinephrine (NE). NE (also called noradrenaline) signals alert and has different roles in the body and the brain. In the body, it induces the mobilization of energy resources through the sympathetic branch of the autonomous nervous system (S-ANS). The S-ANS is stimulated by HT neurons (alerted by CeA) yielding NE secretion from the adrenal medulla. The resulting effects include increased heart rate, blood pressure and blood flow to major organs (e.g., the brain, heart, muscles), pupil dilation, accelerated respiration, etc. In the brain, NE neurons are primarily located in the locus coeruleus (LC), a small bilateral brainstem nucleus, and in a few additional brainstem nuclei (e.g., in the NTS). The LC is innervated by a wide range of regions including cortical valence areas, the CER, and innate-related nuclei (including the amygdala CeA, the HT, and the SC), and projects extensively to virtually all brain areas (except the BG, where DA supports alerts). It has particularly strong projections to mPFC and to areas involved in spatial attention such as the parietal cortex.
NE is commonly released after the real occurrence of a surprise, but can also result from prediction of alert states (e.g., when you get into a situation known to be dangerous). Valence areas are key mediators in both cases.
NE is excitatory via alpha1 and beta1-3 NE receptors (NERs, also denoted adrenorecep- tors (ARs)), and suppressive via alpha2 NERs (Gi/o). Here we present a novel assignment of roles to these receptors.
The affinity of beta NERs to NE is higher than that of alpha1 NERs, and they cou- ple to Gs, which supports immediate execution, while alpha1 NERs couple to Gq, which
48Note that innate-triggering sensory input would trigger innate execution regardless of whether it is ex-
pected or surprising. However, expected innate execution would not yield the alert N mode, which is an adaptive response.
49The PFC area that receives this flow is a vmPFC area called infralimbic (IL) mPFC in rodents, roughly
supports extended execution. Beta NERs are mostly expressed in the sensory and alert net- works, while alpha1 NERs are mostly expressed in the DM network and in HT PVH CRH neurons [Goldman-Rakic et al., 1990]. Thus, beta NERs support immediate responses, in- cluding innate (e.g., cardiac) ones, while alpha1 NERs support adaptive decision making. Alpha1 NERs are also essential for the transient excitatory effect of GABA during alerts (see above).
The affinity of alpha2 NER to NE is greater than that of alpha1 and beta NERs [Arnsten and Pliszka, 2011], which points to a role in automated responses (suppressing firing neu- rons after a transition) and low alert situations (e.g., extended alert, below). According with this role, alpha2 NERs act as autoreceptors to suppress ongoing LC NE release. Alpha2 NERs are colocated with HCN channels and close them [Wang et al., 2007]. HCN channels are expressed only in response network pyramids [Sheets et al., 2011] and support repeated firing at slow rates (i.e., the automated mode). Alpha2 NERs may also act in the initial stages of alerts to pause the ongoing task to promote attention to the alert. NE opposes the ongoing task via its mutual suppression of DA and SER [Guiard et al., 2008, Tassin, 2008]. In summary, innate+ activation yields NE, which recruits energy, pauses ongoing ac- tivity, enhances sensory inputs, and widely excites the predecision networks to induce an acute response.