Thursday, July 04, 2013

Yale Team Finds Nicotinic Receptor Essential for Cognition — and Mental Health

Prefrontal networks are responsible for forming and holding coherent thoughts (a process that is impaired in schizophrenia), and it has been shown in this study that nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex.
Working memory, the mind’s mental sketch pad, depends upon the proper functioning of a network of pyramid-shaped brain cells in the prefrontal cortex, the seat of higher order thinking in humans. To keep information in the conscious mind, these pyramidal cells must stimulate each other through a special group of receptors. The Yale team discovered this stimulation requires the neurotransmitter acetylcholine to activate a specific protein in the nicotinic family of receptors — the alpha-7 nicotinic receptor.
This is an interesting study - and it demonstrates again the importance of the prefrontal cortex in nearly all forms of higher order cognition.

Tomorrow, I will share an article that suggests that early life stress can predict a decrease in medial prefrontal activation and cause a shift from internally to externally guided decision-making. This study will have real implications for understanding how developmental trauma affects adult cognition and locus of control.

Yale team finds nicotinic receptor essential for cognition — and mental health

By Bill Hathaway
July 1, 2013

Nicotinic alpha-7 receptors (indicated by red arrowheads) are next to a synapse between two brain cells in the prefrontal cortex. Stimulation of the nicotinic alpha-7 receptors allows the cells to communicate and thus generate higher cognition. 
(Image from Dr. C. Paspalas, Yale University)

The ability to maintain mental representations of ourselves and the world — the fundamental building block of human cognition — arises from the firing of highly evolved neuronal circuits, a process that is weakened in schizophrenia. In a new study, researchers at Yale University School of Medicine pinpoint key molecular actions of proteins that allow the creation of mental representations necessary for higher cognition that are genetically altered in schizophrenia. The study was released July 1 in the Proceedings of the National Academy of Sciences.

Working memory, the mind’s mental sketch pad, depends upon the proper functioning of a network of pyramid-shaped brain cells in the prefrontal cortex, the seat of higher order thinking in humans. To keep information in the conscious mind, these pyramidal cells must stimulate each other through a special group of receptors. The Yale team discovered this stimulation requires the neurotransmitter acetylcholine to activate a specific protein in the nicotinic family of receptors — the alpha7 nicotinic receptor.

Acetycholine is released when we are awake — but not in deep sleep. These receptors allow prefrontal circuits to come “online” when we awaken, allowing us to perform complex mental tasks. This process is enhanced by caffeine in coffee, which increases acetylcholine release. As their name suggests, nicotinic alpha-7 receptors are also activated by nicotine, which may may help to explain why smoking can focus attention and calm behavior, functions of the prefrontal cortex.

The results also intrigued researchers because alpha-7 nicotinic receptors are genetically altered in schizophrenia, a disease marked by disorganized thinking. “Prefrontal networks allow us to form and hold coherent thoughts, a process that is impaired in schizophrenia,” said Amy Arnsten, professor of neurobiology, investigator for Kavli Institute, and one of the senior authors of the paper. “A great majority of schizophrenics smoke, which makes sense because stimulation of the nicotinic alpha7 receptors would strengthen mental representations and lessen thought disorder.”

Arnsten said that new medications that stimulate alpha-7 nicotinic receptors may hold promise for treating cognitive disorders.

Publication of the PNAS paper comes on the eve of the 10th anniversary of the death of Yale neurobiologist Patricia Goldman-Rakic, who was hit by a car in Hamden Ct. on July 31, 2003. Goldman-Rakic first identified the central role of prefrontal cortical circuits in working memory.

“Patricia’s work has provided the neural foundation for current studies of molecular influences on cognition and their disruption in cognitive disorders,” said Arnsten. “Our ability to apply a scientific approach to perplexing disorders such as schizophrenia is due to her groundbreaking research.”

Yang Yang and Min Wang of Yale are lead author and co-senior authors, respectively. Constaninos D. Paspalas, Lu E Jin and Marina R. Picciotto are other Yale authors.
Here is the abstract and introduction to the full article, available for free online.

Full Citation:
Yang Yang, Constantinos D. Paspalas, Lu E. Jin, Marina R. Picciotto, Amy F. T. Arnsten, and Min Wang. (2013, Jul 1). Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. PNAS: doi: 10.1073/pnas.1307849110

Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex

Yang Yanga, Constantinos D. Paspalasa, Lu E. Jina, Marina R. Picciottob, Amy F. T. Arnstena, and Min Wanga


The cognitive function of the highly evolved dorsolateral prefrontal cortex (dlPFC) is greatly influenced by arousal state, and is gravely afflicted in disorders such as schizophrenia, where there are genetic insults in α7 nicotinic acetylcholine receptors (α7-nAChRs). A recent behavioral study indicates that ACh depletion from dlPFC markedly impairs working memory [Croxson PL, Kyriazis DA, Baxter MG (2011) Nat Neurosci 14(12):1510–1512]; however, little is known about how α7-nAChRs influence dlPFC cognitive circuits. Goldman-Rakic [Goldman-Rakic (1995) Neuron 14(3):477–485] discovered the circuit basis for working memory, whereby dlPFC pyramidal cells excite each other through glutamatergic NMDA receptor synapses to generate persistent network firing in the absence of sensory stimulation. Here we explore α7-nAChR localization and actions in primate dlPFC and find that they are enriched in glutamate network synapses, where they are essential for dlPFC persistent firing, with permissive effects on NMDA receptor actions. Blockade ofα7-nAChRs markedly reduced, whereas low-dose stimulation selectively enhanced, neuronal representations of visual space. These findings in dlPFC contrast with the primary visual cortex, where nAChR blockade had no effect on neuronal firing [Herrero JL, et al. (2008) Nature 454(7208):1110–1114]. We additionally show that α7-nAChR stimulation is needed for NMDA actions, suggesting that it is key for the engagement of dlPFC circuits. As ACh is released in cortex during waking but not during deep sleep, these findings may explain how ACh shapes differing mental states during wakefulness vs. sleep. The results also explain why genetic insults to α7-nAChR would profoundly disrupt cognitive experience in patients with schizophrenia.

Acetylcholine (ACh) acts through a variety of nicotinic and muscarinic receptors to modulate wakefulness (1–3) and orchestrate attention-related circuits in the brain (4). It is released during wakefulness and rapid eye movement (REM) sleep (1, 3), exciting the thalamus and cortex (2, 3, 5) and allowing conscious experience (6). Despite the established importance of ACh in cortical function, there is very little known about its effects at the cellular level in cognitively engaged circuits. One study of the primate primary visual cortex [V1 (7)] showed attentional modulation by muscarinic but not nicotinic receptors. However, there have been no physiological studies of cholinergic actions in higher association cortices in primates, even though behavioral data indicate that ACh is essential for the working memory (WM) functions of the dorsolateral prefrontal cortex (dlPFC) (8), a highly evolved brain region that subserves mental representation and executive function as well as the reactivation of long-term memories onto the “mental sketch pad” (9, 10).

Goldman-Rakic and colleagues discovered the cellular basis of the spatial WM functions of primate dlPFC (9). Lesions to the principal sulcal dlPFC in monkeys permanently impair spatial WM performance, whereas physiological recordings from this area have revealed “delay cells” that generate mental representations of visual space even when stimuli were no longer present in the environment (9). These delay cells can maintain information in temporary storage to guide prospective motor acts, thus integrating perception and action (11). These neurons maintain persistent firing throughout the delay period when information is held in WM, firing selectively for a “preferred direction” to create visuospatial representations (Fig. 1 A–C). Goldman-Rakic uncovered the cellular basis of these spatial WM functions and the circuitry underlying visuospatial representation (Fig. S1) (9): Neurons in dlPFC receive highly processed visuospatial information  from the parietal association cortex, and layer III dlPFC pyramidal cell microcircuits excite each other to maintain persistent firing across the delay. Persistent firing also may involve reciprocal excitation with longer-range cortical–cortical circuits, for example, with the parietal association cortex (12). The spatial tuning of dlPFC delay cells is refined by GABAergic lateral inhibition from local basket and chandelier cells (Fig. S1). Recent studies have shown that the persistent firing of delay cells relies on glutamate NMDA receptors (NMDARs), including those with NR2B subunits, which are localized in the postsynaptic densities of glutamatergic synapses on spines in deep layer III (13). These pyramidal cells expand greatly in primate evolution (14), and are especially afflicted in schizophrenia (15, 16) and Alzheimer’s disease [AD (17)].

A variety of higher cognitive disorders are associated with impaired dlPFC function and genetic insults to nicotinic α7 receptors (α7-nAChRs) and/or NMDAR signaling. There is extensive evidence linking genetic alterations of α7-nAChR to schizophrenia and attentional deficits (18, 19), including alterations at the transcription level (20). Recent data have also shown that α7-nAChR expression depends on neuregulin, another molecule linked to schizophrenia (21), and that smoking in schizophrenia may be a form of self-medication, normalizing expression of α7-nAChRs (22). More recent studies have linked α7-nAChRs to autism (23), attention deficit hyperactivity disorder [ADHD (24)], and AD (25), suggesting that a variety of dlPFC disorders are linked to alterations in α7-nAChR signaling. α7-nAChR agonists are currently under development as potential therapeutic treatments for these disorders, based in part on animal studies showing that systemic administration of α7-nAChR agonists can rescue WM deficits induced by NMDAR blockade (26, 27). However, the location and physiological roles of α7-nAChR in dlPFC circuits had not been known. The current study used electron microscopy and recordings from cognitively engaged monkeys to reveal α7-nAChR localization and actions in primate dlPFC. We report that α7-nAChRs are situated in the postsynaptic density of glutamatergic synapses in deep layer III of dlPFC, and that α7-nAChR stimulation is essential for the excitation of NMDAR-mediated WM circuits.
Read the whole article.
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