Working memory and neuronal calculus

The world offers an awesome, indescribably magnificent profusion of sensory riches. For our meager mortal brains, however, trying to process this deluge of information is akin to taking a drink from Iguaçu Falls: it's tremendously inefficient, and you will likely be violently ripped from your precipice and vanish in a ferocious torrent of natural wonder.

Because the world is too rich for our brains to process at once (or even in a lifetime), we are equipped with mechanisms that restrict the avalanche of information to a manageable trickle. At the level of the brain, this restrictive bottleneck is referred to as attention; when we attend to a certain stimulus, we select it for more comprehensive processing, while relegating the rest to a relatively superficial survey. Importantly, attention endows a capacity limitation onto our brains, not our sensory organs, which latter detect a remarkable embarrassment of sensory details. For example, the sensory neurons on the bottom of your feet are well aware of the pressure exerted by the floor, but you were probably not actively thinking about it until this sentence directed your attention to the sensation.

If our processing ended with attention, we would conduct our lives strictly from information received at the present instant, without any internal state of the mind or abstract thought. But instead of flitting whimsically in and out of our brain, information selected from the world by mechanisms of attention gain access to our working memory, which temporarily holds onto this information for detailed evaluation. For example, when ordering a pizza for delivery, you read from the menu "4-1-5, 6-9-5, 1-6-1-5," hold the sequence in your head, and punch it into your phone. In the interim between reading and dialing, the digits were stored in your working memory, and likely quickly forgotten once you heard the first ring and the number was no longer relevant. In more complex situations, the information in our working memory is the basis for decisions and planning of elaborate behavior, and is thus a critical component in many cognitive processes associated with human "intelligence," such as language.

So what is the neural manifestation of working memory? What happens in your brain between reading and dialing the pizza delivery number? Working memory is dependent on the prefrontal cortex (PFC), which is the region at the very front of the brain, directly behind the forehead. In the monkey PFC (and presumably in that of humans), there are neurons that seem to exhibit many properties of working memory; that is, they are activated by a specific stimulus, and if the stimulus will soon be relevant, they temporarily remain activated even after the stimulus disappears. For example, if a monkey must remember the location of a flash of light for a period of 4 seconds, a certain population of neurons will experience a surge in action potentials in response to the light, and proceed to fire at this elevated rate through the 4-second delay period. When the animal reports the stimulus location, the latter information is no longer relevant, and the population of neurons shuts down accordingly. Such neurons are said to exhibit persistent activity (also called "delay period" activity). Persistent neural activity is thought to represent information about a stimulus even after it is gone, thus reflecting the temporary storage of information, i.e. our working memory.

Persistent neural activity presents an interesting computational complication: action potentials are brief electrical pulses, so how does the system interpret a tonic, persisting pattern of neural activity? In a process called temporal integration (theoretically similar to mathematical integral calculations), the system accumulates information over a certain window of time and "remembers" the sum as a pattern of neural activity. That is, the network dynamics of the circuit can integrate a flurry of brief electrical pulses, and translate the sum into a persistent change in activity. One fundamental question is how the circuitry of neural integrators accomplishes this computational feat, which appears to be so fundamental to working memory.

Emre Aksay of Weill Cornell Medical College, in collaboration with David Tank at Princeton University, recently published a study in Nature Neuroscience that investigated this issue in the neural integrator that controls eye movements in goldfish (the goldfish "oculomotor integrator"). Although goldfish eye movement is not the most intuitive place to study working memory, the goldfish oculomotor integrator is a particularly tractable neural integrator, and may thus provide a framework for understanding similar mechanisms in, for example, our PFC.

Like most animals, goldfish spontaneously move their eyes around, fixating on items of interest (e.g. my finger on the glass of their tank). In order to keep the eyes in that stable, fixed position, the animal must have a sustained neural representation (i.e. a memory) of its eye position, which guides and maintains the activation of the appropriate eye muscles (even if my finger is briefly removed). The oculomotor integrator generates this internal representation by integrating the action potentials of neurons which signal changes in eye position.

When a goldfish is looking to the right, the neurons on the right side of the integrator increase their firing rates (behavior characteristic of a positive feedback system), while those on the left decrease their firing rates. Presumably, the positive feedback occurring on the right is critical for generating persistent firing, thereby enabling integration. However, the connective logic of the circuit that mediates this positive feedback is unknown.

It is known that the oculomotor integrator is a bilateral circuit, with two populations of excitatory neurons (one on each side of the brain); these populations are connected primarily by inhibitory neurons. In light of this neuroanatomy, there are two feasible mechanisms that may mediate positive feedback: a) disinhibition from (in this example) the left side of the integrator or b) excitatory connections between cells on the right side of the integrator.

By using drugs that targeted either excitatory or inhibitory neurons, Aksay and Tank sought to dissect the circuitry of the integrator and solve this dilemma. They found that the persistent activity of the integrator that underlies eye fixation did not require inhibitory neurons, but did require the excitatory connections. However, the inhibitory connections between the right and left sides of the integrator appeared to be important for coordinating the two sides, ensuring that only one has persistent activity at any one time (and thus that the eye only moves in one direction at a time).

And now for the tantalizing extrapolations to which neuroscience lends itself so wonderfully: although the persistent neural activity of discrete neural integrators, (holding a specific set of information in your working memory), does not require inhibitory pathways, the coordination between different integrator circuits (i.e. representations of different sets of information) does. The cornucopia of information presented by our surroundings may require these inhibitory connections to help liaise our working memory at a local level, lest the mayhem of our welter world prevail.

Got nicotine?

As a pledge-signing member of my elementary school's rigorous D.A.R.E. program, I was regularly exposed to horrific photographs of blackened lungs and deteriorating hearts, and was utterly convinced that cigarettes ravaged and destroyed everything they touched. Thus when my dad started smoking when I was about 5, I (with my mom's encouragement) flushed pack after pack down the toilet until he quit. I still do not smoke, and I don't plan to, but I have grown a bit more discerning with respect to sensationalist demonization of various pleasure-enhancing drugs.

It turns out that of the 4,000 or so compounds in tobacco smoke, including a variety of carcinogens, and toxins such as carbon monoxide, heavy metals, and cyanide, at least one ingredient actually has some beneficial effects: nicotine. There is a large body of research showing that nicotine, the ingredient that drives people to addiction, improves cognitive function in humans and laboratory animals. The most robust effect demonstrated in human smokers is an enhanced ability to sustain attention to a task for a prolonged period of time, an ability inextricably linked to learning and memory. Of course, learning and memory involve a number of processes (acquisition, encoding, storage, and retrieval), but the ability to concentrate on particular stimuli and screen out the rest is critical for the success of this operation.

Nicotine's beneficial effects on these "higher" cognitive functions have prompted efforts to develop nicotinic treatments for diseases associated with cognitive impairment, such as Alzheimer's disease, Parkinson's disease, attention deficit/hyperactivity disorder, and schizophrenia. However, this area of drug development is impeded by the complexity of nicotine's actions, including the observation that cognitive improvements have only been reliably detected in either smokers or the cognitively impaired. In contrast, nicotine tends to have deleterious effects on cognitive performance in "normal" non-smokers. (Another factor hampering the development of nicotine-based therapies is that they offer pharmaceutical companies little potential for financial gain, as nicotine sources are easy to come by.)

So how does nicotine affect cognitive function? First, a bit about how neurons communicate with each other. Some people may be able to skip the next few paragraphs (which I've distinguished with altered formatting), but I've included them anyways because it's important to have at least a rough idea of this process in order to understand how nicotine works in our brains.

Neurons are functionally integrated in expansive neural networks, with each neuron receiving up to thousands of inputs from other neurons. However, the vast majority of neurons* are not actually physically connected to one another; there is a tiny gap that separates neurons, called a synapse.

When a neuron is activated, an electrical pulse (an action potential) travels down its membrane; the neuron is said to "fire" an action potential. When the action potential reaches the end of the neuron, it cannot traverse the synapse, but instead induces the release of chemicals which can. Once liberated from the "pre-synaptic" neuron, these chemicals (called neurotransmitters) navigate across the synapse and bind to specific receptors on the "post-synaptic" neuron. Once bound, the neurotransmitters induce one of many physiological changes: they can make it easier to fire an action potential ("excitatory" neurotrasmitters), more difficult to fire an action potential ("inhibitory" neurotransmitters), or modulate the firing rate or other behavioral properties of the cell.

An overwhelming number of pre-synaptic neurons, all of which are sources of neurotransmitters, impinge on a single post-synaptic neuron, yet the latter responds with a binary decision: fire or don't fire. The cell creates order from this chemical deluge by performing a complex, time-dependent summation of all of its inputs; if it receives a sufficient number of excitatory inputs within a reasonable time window, it will fire an action potential and release its own neurotransmitter, passing the information along the circuit.

Each neurotransmitter can bind to a number of complementary receptors. One of the receptors for a neurotransmitter called acetylcholine (ACh) happens to also bind and respond to nicotine, which is not naturally present in the body. Thus when a post-synaptic neuron containing these particular receptors (called nicotinic ACh receptors, or nAChRs) is exposed to nicotine (as in when someone smokes a cigarette), it behaves as if it has been influenced by ACh; i.e. to an individual nAChR, nicotine and ACh are indistinguishable.

However, there is a crucial difference at the circuit level: ACh is regulated by your body, so it is typically released in small amounts by specific subsets of neurons at any given time. In contrast, nicotine, entering your body from an external source, can potentially act at all nAChR-bearing neurons simultaneously, leading to widespread activation and an assortment of consequences (including the release of other neurotransmitters, such as dopamine, endorphins, and ACh itself).

Turns out that the prefrontal cortex (PFC), a brain structure with a critical role in learning and memory, contains an abundance of nAChRs. This area receives information from all of the senses, and aids the learning process by directing attention to a limited set of input streams at a time. Like many cortical synapses, the excitatory synapses in the PFC are plastic, capable of undergoing systematic changes in synaptic strength/efficacy.

These changes are thought to underlie the processing and storage of information in neural circuits, and for that reason take place in a functionally relevant manner (i.e. one that is dependent on the activity of that particular synapse). Specifically, the robustness and direction (stronger or weaker) of the change in synaptic strength is dependent on the precise timing of pre-synaptic inputs and post-synaptic action potentials (also called "spikes"). This temporal correlation gives the process its name: spike-timing-dependent plasticity (STDP). According to the rules of STDP, a synapse with a high temporal correlation between pre-and post-synaptic activity will strengthen.

Importantly, excitatory synapses in the PFC change during working-memory related tasks, implicating the PFC in these cognitive behaviors. It is likely that nicotine's effects on attention and working memory are effectuated at the nAChR-containing synapses of the PFC, but the mechanistic changes are unknown. Moreover, it is unclear how these synaptic changes affect the functional properties of the circuit underlying these cognitive processes.

A group from Amsterdam, led by Huibert Mansvelder, published a study that explored the cellular and synaptic mechanisms of nicotine's actions in the most recent issue of Neuron, with a focus on how nicotine affects STDP in the PFC.

The scientists cut rat PFCs into slices, and induced STDP by electrically stimulating pre- and corresponding post-synaptic cells simultaneously. After repeating this paired stimulation (50 times), the synapse becomes "potentiated," meaning the pre-synaptic neuron becomes more effective at stimulating the same post-synaptic cell than it was before the procedure; i.e. the synapse is "stronger".

When nicotine was applied to the solution bathing the slice, this potentiation failed to occur. The blockade of STDP could be overcome, however, by increasing the electrical activity of the post-synaptic cell, indicating that the pairing procedure was less effective, but not defunct. The group found that nicotine's net effect was to enhance the release of a major inhibitory neurotransmitter, called GABA. In the context of the synapse, the post-synaptic neuron would thus be bombarded by copious amounts of GABA, which would then dominate the input summation. These actions decrease the likelihood that the post-synaptic neuron will fire, thereby interfering with the concomitant activation of both synaptic partners and interfering with STDP.

So how does impeding STDP, a process thought to provide the cellular foundation for an adaptive nervous system, enhance cognitive function in certain individuals? This question brings us back to attention--the ability to concentrate on relevant stimuli while ignoring that which is irrelevant. During PFC-based cognitive behaviors, the neural activity in the PFC may increase to distracting levels. By enhancing inhibitory neurotransmission, nicotine may enhance the "signal-to-noise" ratio, thereby improving attention selectivity. This may be particularly beneficial to smokers who are accustomed to high nicotinic stimulation, as well as individuals with cognitive impairment, as both these groups are functioning suboptimally in the absence of nicotine.

And what about normal individuals, whose cognitive functioning is often impaired with nicotine? Such "drug-free" individuals are probably already performing at or near their optimal level of performance. As a result, increasing nicotinic stimulation and interfering with STDP will have negative effects in most situations. It is possible, however, that even in "normal" individuals, nicotine may enhance cognitive function under extreme task demands. During such tasks, which necessitate intensified attention over a prolonged period of time, optimal performance may be facilitated by nicotinic stimulation.



*My explanation of synaptic transmission describes, specifically, a chemical synapse. These are the predominant form of synapses in the brain, but neurons can also be connected by channels called "gap junctions." The openings of these channels allow ions to flow from one neuron to the next, enabling electrical signals to pass directly between neurons. This type of connection is called an electrical synapse, and the transmission of information is much more rapid than at chemical synapses.