Biodata name of the Nominee : Birendra Nath Mallick 2

Fig. 7

This part of Mallick’s findings may be summarised as “REM sleep deprivation increases NA in the brain which acted on alpha1A adrenoceptor, modulates intracellular calcium which increases Na-K ATPase activity due to dephosphorylation resulting in increased neuronal excitability, which ultimately causes REM sleep deprivation induced disorders” (Fig. 8).

Fig. 8



iv) Mechanism of REM sleep loss associated decrease in body temperature :

Preoptic area is known to regulate sleep-wakefulness and body temperature. Mallick’s group first showed that such regulation can be independent of each other and proposed that one of the functions of sleep is to maintain the body temperature within physiological limit (Mallick and Alam, 1991; 1993; Alam and Mallick, 1994). His studies brought out a unique mechanism that NA acting on the medial preoptic area, regulates sleep, wakefulness and body temperature by acting on α-2, β and α-1 adrenoceptor subtypes, respectively (Mallick and Alam, 1992); such mechanism is likely to exist for other brain mediated functions. Subsequently using micro-iontophoresis his group confirmed that the temperature sensitive neurons in the preoptic area do possess α-1 adrenoceptors (Mallick et al., 2002). They also showed that the action of cholinergic inputs in the preoptic area was mediated through muscarinic receptors (Mallick and Joseph, 1997) and unlike the adrenergic inputs, although the cholinergic inputs in the preoptic area may not have dissociated effects on sleep-waking and body temperature, the cholinergic and adrenergic inputs integrate in the preoptic area for the regulation of those functions (Mallick and Joseph, 1998). Additionally, very recently it has been shown that the GABA-ergic neurotransmission in the preoptic area is spontaneously active for modulation of the hypnogenic functions, including REM sleep, and the action is mediated through GABA-A receptor (Ali et al., 1999). They identified specific adrenergic and GABA-ergic receptor subtypes on warm and cold thermosensitive neurons in the preoptic area. Although both the temperature sensitive neurons in the preoptic area express similar response to adrenergic inputs (Mallick et al., 2002), warm and cold sensitive neurons express opposite response to GABA (Jha et al., 2001) and to inputs from waking area in the brain stem (Mallick et al., 2004). The findings led them to propose GABA acts pre-synaptically on the NA-ergic terminals projecting on the warm sensitive neurons but post-synaptically on the cold sensitive neurons (Fig. 9) for finer thermoregulation (Jha and Mallick, 2009).

Fig. 9



These findings help explaining NA mediated mechanism of thermoregulation during different conscious states including sleep-waking-REM sleep and REM sleep loss, when the NA level is reported to vary in the body and the brain (Fig. 10). Also, in practice, these findings from Mallick’s group especially their insight towards understanding on pre-synaptic modulation of neurotransmitter release for regulation of physiological parameters has significantly helped treating and ameliorating symptoms in Crisponi syndrome patients (Herholz et al., 2010).

Fig.

v) REM Sleep Prevents Apoptosis :

Since REM sleep deprivation increases Na-K ATPase activity, it was proposed that neuronal morphology and size are likely to be affected after deprivation and in extreme case neuronal survivability is likely to be compromised. It was indeed found that REM sleep deprivation altered neuronal morphometry and the effects were different on cholinergic, adrenergic, GABA-ergic and serotonergic neurons and interestingly the effects were also mediated by NA acting through α1 adrenoceptors (Majumdar and Mallick, 2005; Ranjan et al., 2010). Further, REM sleep loss increases apoptosis and damages structural proteins in neurons suggesting prevention of neuronal apoptosis is a potent likely function of REM sleep (Majumdar et al., 2006). Subject to confirmation, they also proposed that age related neurodegenerative diseases may have a bearing on REM sleep loss because ageing is associated with REM sleep loss and the effects may primarily be mediated by elevated NA level in the brain.

vi) Homeostasis maintenance - Role of glia :

As it was confirmed that the NA increases Na-K ATPase activity, which would alter the Na and K ionic exchanges, it was not clear how the ionic homeostasis would be maintained. In an attempt to solve this riddle, Mallick’s group then found that NA affects the glial Na-K ATPase activity in a manner opposite to that of the neuronal Na-K ATPase (Baskey et al., 2009) leading them to propose the model in Fig 11.

Fig 11



C) Structure of alpha1A adrenoceptor :

REM sleep loss induced effects were mediated by NA acting on α1 adrenoceptors. For better understanding of the action of NA e.g. for drug development, etc one needed to know the structure of adrenoceptor. Using in silico homology modelling Mallick’s group modelled the α1 adrenoceptor active site (Vijayan, et al., RCSB ID : rcsb 035534; PDB ID : code 2F75); further they identified the amino acid residues most crucial for binding of NA and its agonist/antagonist (Ramachandran et al., 2007).

All the findings mentioned here, behavioural to cellular to molecular levels, have been summarized in Fig. 12. It shows non-cessation of NA-ergic REM-OFF neurons in LC would reduce REM-sleep and increase NA in the brain. Alternatively if REM sleep is prevented, NA-ergic REM-OFF neurons continue firing instead of being silent resulting increased NA or, if NA as such is increased in the brain by any other means, it would prevent REM sleep. Thus, increased NA holds key for inducing and mediating REM sleep loss and associated symptoms - pathological conditions.
Fig. 12


D) Marker for REM Sleep deprivation :

Although REM sleep serves such important function and its loss affects several systems, there is no

easy biomarker for identification and quantification of REM sleep loss. We have identified a blood protein (~200 KDa) which decreases after REM sleep deprivation. The protein was purified, sequence analyzed and identified as alpha1-Inhibitor3, a negative acute phase response protein (US Patent; manuscript under preparation). This protein has a potential to be exploited as a marker and may be used for treating REM sleep loss induced effects.
Finally, the work done by the group led by Biren Mallick can be summarized as in Fig 13.

Fig 13