CASACIÓN 895-2016 LIMA

1.3.3.1.“Tonic” vs “Burst” mode

Thalamocortical cells can fire action potentials in two very distinctive fashions, namely thetonicandburstfiring modes. When in tonic mode, cells fire

the other hand, cells fire closely packed groups of action potentials, each group separated by periods of relative inactivity (Figure 1.7b) (Jahnsen and Llinas, 1984). What determines the firing mode of a thalamocortical cell is the state of one of its many membrane conductances; namely, the Ca2+

conductance. This conductance (also known asIT, because it involves T-type Ca2+channels (Sherman, 2001)) is dependent on the voltage (and its

duration) of the cell’s membrane.IT becomesinactivatedat depolarised membrane potentials of above –55mV that last more than ~100ms. A strong depolarisation of the cell (e.g. due to a stimulus presentation in its receptive field) whileITis inactivated results in the generation of trains of single action potentials (tonic firing mode) (Jahnsen and Llinas, 1984). When the cell’s membrane, however, hyperpolarises at potentials below –65mV, and for periods longer than ~100ms,ITbecomesde-inactivated.While in that state, a strong enough incoming depolarisation canactivate IT, allowing the influx of Ca2+, resulting in a low-threshold spike (a brief depolarisation of ~30mV) ridden by a burst of closely packed action potentials (burst firing) (Jahnsen and Llinas, 1984). In order for a cell to fire in bursts, therefore, theIThas to first become de-inactivated, via a slightly lengthy hyperpolarisation, and then activated by a strong, and preferably brief, depolarisation.

Figure 1.7: Schematic representation of tonic (1.7a) and burst (1.7b) activity

1.3.3.2. Functional role of firing mode in the thalamocortical pathway

Earlyin vivoinvestigations reported that tonic firing in thalamocortical cells was more prominent during periods of wakefulness or REM sleep, whereas burst firing was evident only during deep sleep stages or deep anaesthesia, when thalamocortical cells are typically hyperpolarised (e.g. Livingstone and Hubel, 1981; Steriade and McCarley, 1990; Steriade, Contreras, Curro Dossi and Nunez, 1993; Steriade, McCormick and Sejnowski, 1993). This led to the assumption that tonic firing is the main sensory-relaying firing mode of the thalamocortical relay system, whereas burst firing, and especially when rhythmic, represents a mode of sensory disengagement during which no sensory input is relayed to cortex (e.g. see Steriadeet al., 1993). More specifically, the rhythmic bursting of thalamocortical cells was thought to represent a way by which the cortex was signalled that the relaying of information was suspended. Doing so by means of rhythmic bursts, rather than with a total cessation of firing, offers a clear functional advantage, for the

1.7a

latter could also signal the lack of stimulation (Sherman and Guillery, 2001). Nonetheless, even though it is now generally accepted that the role of rhythmic bursting is associated with stages of sleep and the interruption of sensory transmission, more recent evidence suggests that burst firing in thalamocortical cells may also have an important functional role in awake states too (see below).

1.3.3.3. Mode of firing and transmission of sensory information

Contrary to initial belief that bursts only occur during non-REM sleep and anaesthesia, bursts have also been reported in awake animals (Guido and Weyand, 1995, Nicolelis, Baccala, Lin and Chapin, 1995; Ramcharan, Gnadt and Sherman, 2000, Fanselow, Sameshima, Baccala and Nicolelis, 2001). In the awake state, and in the absence of stimulation, bursts tend to be relatively infrequent and to possess little or no rhythmicity, occurring instead at random intervals. In the presence of stimulation, however, bursts stop occurring randomly and begin to follow the presentation rate of the stimulus (Sherman, 1996). This demonstrated that, similarly to tonic firing, burst firing is also capable of relaying sensory information. Indeed, burst firing in thalamocortical cells (LGN cells in particular) has been found to encode sensory information, and drive post-synaptic cortical cells, at least as effectively as tonic firing (Reinagel, Godwin, Sherman and Koch, 1999). Not surprisingly however, the properties of tonic and burst firing modes are quite different with regard to the relay of information. That is to say, even though the quantity of information relayed by these firing modes could be the same, the quality of the information relayed appears to be substantially different. When in tonic mode, cells

respond to sensory stimulation in a linear fashion reflecting faithfully the rate of the stimulus presentation (Sherman, 1996). However, the linear

representation of the stimulus is accompanied by high levels of background activity. Burst firing, on the other hand, is characterised by much lower levels of background noise, but responses to sensory stimulation are less linear and considerably poorer in temporal resolution (Guido, Lu and Sherman, 1992; Guido, Lu, Vaughan, Godwin and Sherman, 1995; Mukherjee and Kaplan, 1995). As a consequence, whereas a cell when firing tonically would provide different responses for stimuli with different characteristics, such stimuli would generate highly similar responses in the same cell when bursting. A classic demonstration of the above comes from the responses of dLGN cells to the visual presentation of a drifting sinusoidal stimulus in the cat. Whereas the responses of tonically firing dLGN cells resemble the sine, bursting dLGN cells only respond to the beginning of each cycle of the sine, resulting in a much less sinusoidal pattern of responses (Sherman, 1996; also see

Sherman and Guillery, 2001). This means that a cell in both tonic and burst firing can inform the postsynaptic cell of the occurrence of a stimulus, but, when in burst firing, most information about the characteristics of that stimulus is omitted.

Functionally, the above differences between tonic and burst firing result in certain advantages of the one over the other in the transmission of

information, with regard to certain sensory parameters. For example, due to the faithful and linear representation of its input, tonic firing is optimal for the detailed analysis of sensory stimulation. On the other hand, burst firing may

lack linearity but, due to its much better noise-to-signal ratio, it is the ideal firing mode for the detection of weak or sudden stimuli that would be, most likely, missed by the “noisy” tonic firing. More specifically, because burst-firing cells respond better to middle- than high-frequency stimulus presentations, they are particularly good at the detection of abrupt, rather than gradual, changes in the environment (Guido, Lu, Vaughan, Godwin and Sherman, 1995; Guido and Weyand, 1995).

With regard to attention, it is apparent from the above that a continuous interchange between the two firing modes would be necessary in order for most attentional behaviours to take place. For example, when attention needs to be paid to a particular area of the sensory field where stimulation is

expected, thalamocortical cells representing that area may initially start firing in burst mode so that to enhance the detection of the upcoming stimulus. As soon as the stimulus is detected, the firing mode can switch to tonic, which will enable the more detailed representation of that stimulus. In other words, even though tonic activity corresponds to the main and lengthier part of an

attentional behaviour (the detailed perceptual analysis of the stimulation), it is burst activity that often initiates that behaviour. Burst firing, in this context, can be seen therefore as a “wake up call” (Sherman, 1996; 2005) to cortical

sensory areas, informing them of new incoming information, thus preparing them for its subsequent delivery in tonic mode.

Further supporting evidence for the idea that burst mode acts as a “wake up call” comes from the observation that a thalamocortical burst, and more

specifically the first action potential in such a burst, is more effective at

activating post-synaptic cortical cells than any individual thalamocortical tonic action potential (Swadlow and Gusev, 2001). This is because whereas post- synaptic effects of tonic action potentials are likely to sufferpaired-pulse depression, this is not entirely the case for burst action potentials. Paired- pulse depression is the “weakening” of the post-synaptic effects of an action potential that arrives shortly after another action potential (see Castro-

Alamancos and Oldford, 2002; Chung, Li, and Nelson, 2002; Nicolelis, 2002, for examples in the thalamocortcal circuits). The source of this effect is the inability of a cell to recover fully from the first action potential in time to generate an equally strong second one, which as a consequence ends up being weaker (depressed). Given that tonic action potentials come in long continuous sequences and with relatively brief interspike intervals, pair-pulse depression is in constant effect. On the other hand, the first action potential in a burst has to, compulsorily, be preceded by a silent hyperpolarized period of at least 100ms, which is enough time for the cell to recover from the effects of any preceding events (Sherman, 2001). As a consequence, the first action potential in a burst never suffers the effects of paired-pulse depression and can therefore exert maximal effects on post-synaptic cells. In addition, due to their extreme temporal proximity, the remainder of the action potentials in a burst can sum up their post-synaptic effects, and, despite suffering paired- pulse depression, provide a strong overall post-synaptic effect on cortical cells (Sherman, 2001; Swadlow and Gusev, 2001). The temporal proximity of tonic action potentials, on the other hand, is such that while paired-pulse

depression is inevitable, temporal summation of their post-synaptic effects is less likely.