“G EN ES OF H APPIN ESS AND W ELL B EIN G ” IN THE C ON TEXT OF S EARCH A CTIVITY C ON CEPT

The goal of this article is to discuss that the long allele of the serotonin transporter gene that was considered in some publications to be a gene of “happiness” and “well - being” is actually a gene that is responsible for the predisposition to the search activity that by itself contains positive emotional feelings. This statement is confirmed by the comparison of the results of different investigations and helps to solve many contradictions in psychobiology of emotional sensitivity, fear, depression, suicide attempts, of relationships between stressful conditions and well-being.

monozygote (MZ) correlation su ggest that the stable comp onent of w ell-being (trait hap p iness) is largely d eterm ined genetically. H eritability of the stable com p onent of w ellbeing w as accord ing to cited authors about 80%. Unshared environmental effects mu st then accou nt for the rem aining 20% of variance in the stable component of hap piness. Interpersonal emotional relationship s, satisfaction w ith job, goal achievement m ay be reasons of happiness but they also may be the outcome of feeling happ y -behavior and w ell-being prod uce a feed back system. Bartels and Boom sm a (2009) show ed the high heritability (40%-50%) of a subjective w ellbeing (SWB): a total sum of cognitive and em otional reactions of people w hen they compare w hat they have and d o in life w ith their aspirations, need s and expectations. It w as show n that 36%-50% of ind ivid u al d ifferences in subjective w ell-being are accounted for by genetic factors and the rem aining variance is accounted for by non -shared environmental factors.
H ow ever, w hat are the concrete genetic mechanisms that pred isp ose subject to w ellbeing? Tod ay it is p ossible to prop ose an answ er on this question. Accord ing to some investigations (De N eve, 2011) it is a genetic p red isp osition tow ard s the em otional w ell-being and feeling of hap p iness, and the cru cial role in these feelings belongs to the p articu lar serotonin-transp orter gene (5 H TTLPR) that encod es the d istribu tion of a m ood regu lator serotonin (5H T) in brain nerve cells. There are tw o fu nctional versions of this gene called the long one (L) and short one (S), and L prod uces m ore transporter -protein molecules and lead s to more serotonin transporters in neuron cell w alls than S thus provid ing higher activity of the serotonin-d ep end ent brain system that regulates mood and behavior . Accord ing to De Luca et al. (2006), L allele has also tw o versions (A and G) and only the LA is associated w ith the high level of 5 H TTm RN A expression w hile LG is more sim ilar to the S allele that d eterm ines a relatively low level of serotonin transp orter (5H TTm RN A).
Each subject has tw o versions (called alleles) of each gene, one from each parent. As a result some people have tw o S alleles, some have tw o L alleles and other have one L and one S alleles. Those people w ho have at least one L (LA) allele d isplay a general satisfaction w ith their life on 8% m ore often than those w ho d o not have L allele et all, and those w ho have tw o L alleles d isplay such satisfaction on 17% m ore often in comp arison to th ose people w ho have only S alleles. In su bjects w ith L version 35% are very satisfied w ith life, 34% are satisfied w hile in subjects w ith S version only 19% are satisfied (De N eve, 2011).
In parallel w ith the increase of the satisfaction w ith life increa ses the nu mber of people w ho d isp lay the increase of both long (L) alleles from 20% to 35% (De N eve, 2011). At the same time the S alleles are the highest in ind ivid u als w ho are extremely u nsatisfied w ith their life and in these subjects the combination of the S-L and L-S alleles are equally d istributed .
On the other hand , serotonin influences norm al fear (Hariri et al., 2002) that is necessary for the mobilization of bod y resources in the d angerous and ind efinite situ ation. Thus happ iness (emotional w ell being, free exploration and creativity) on the one hand , and a fear in d angerous situation on the other hand are both related to the high activity of the brain serotonin system. H ow is it possible to integrate these d ata in the holistic concept and to avoid contrad ictions betw een w ell-being and fear and at the same time explain how the genetic alleles of the serotonin system interact w ith the environment prod ucing w ell -being?

SEARCH ACTIVITY CON CEPT -MAIN STATEMEN TS
I suppose that the search activity concept can help to solve this problem. This concept w as alread y d iscu ssed in the comprehensive w ay in m any my previous publications (for review see Rotenberg, 2009) and I am going now only to mention its main statements that are most important for the topic of the present article.
By search activity is und erstood activity d esigned to change the situ ation or the subject's attitud e to it in the absence of a d efinite forecast of the results of such activity (i.e., in the case of pragm atic ind efiniteness), but w ith constant m onitoring of the results of such activity. Accord ing to this d efinition certain behavioral categories cannot be linked w ith search activity. This applies to stereotyped behavior having a quite d efinite forecast of results. Panicky behavior d iffers from search activity by the absence of the feed back betw een the activity and its regulation -the results of the activity are not consid ered at any stage and cannot be used for the correction of behavior. Renu nciation of search is opp osite to search behavior and in animals may assure the form of freezing or learned helplessness and in hum ans corresp ond s to d epression and m alad ap tive (neurotic) anxiety.
Search activity is a comp onent of m any d ifferent forms of behavior: self-stimulation in anim als, creative behavior in hu mans, as w ell as exploratory and active d efense (fight/ flight) behavior in all sp ecies. In all these form s of behavior the p robability forecast of the ou tcom e is ind efinite, but there is a feed back betw een the behavior and its ou tcome enabling the su bject to correct his behavior in accord ance to the ou tcom e.
In research cond u cted together w ith V. Arshavsky (for review Rotenberg, 2009) w e fou nd that all form s of behavior w hich includ e search activity increase bod y resistance to the stress and p revents d ifferen t form s of artificial p athology (artificial ep ilep sy, extrap yram id al d isturbances cau sed by neuroleptics, anap hylactoid ed ema, heart arrhythm ia etc.) w hile renunciation of search d ecreases bod y resistance, su p press im mu ne system and pred isposes subjects to the d evelopment of these d isord ers. We suggested that search activity d efend s su bjects from d ifferent som atic d isord ers. In other w ord s search activity safes health.
This statement got recently an unexpected confirm ation in the investigations of authors w ho are not aw are about the search activity concept. Frenkel et al. (2011) investigated the socalled "exceptional p atients", w ho had cancer consid ered uncurable by med ical report and who subsequently became d isease-free or experienced unexplained survival time given the nature of their d isease or treatment. The m ain comm on feature of these p atients w ith d ifferent typ es of cancer (in USA and Israel) w as p ersonal activism . This w as m anifested in taking charge and getting involved in the process of d iagnosis and treatment as w ell as becoming m ore altru istic (it means active in their altruistic attitud es to others). It w as not only an active fight w ith the d isease -it w as also a general responsibility for their ow n life, they w ere d oing the things they love, they had a feeling of the mission in their life. The com mon point of all these behavioral attitud es is search activity.
Exploration and creativity includ es the most relevant realization of search activity and at the same time brings subject a feeling of happiness.
Search activity not only helps subject to cope w ith stressful life events and protects health. The process of search activity by itself d oes not matter w hether it helps to achieve pragmatic goals or not, d etermines a positive feed back betw een behavior and brain m onoamines. It means that d efinite level of brain m onoamines is required to start search activity w hile search activity stimu lates brain monoam ine system s and helps to restore the level of brain catecholam ines that have been used in the process of behavior . Such feed back causes an excitement and feeling of happiness like it happened not only in the process of creativity but also in the process of agitated fight, of goal achieving, of m od eration the environment. It is a very special type of happ iness -it is not a happiness of relaxation after the goal achievement, it is a hap piness caused by the process of achievement.
Search activity in w akefulness is based on the combination of activating (Achacetylcholine and DA -d opam ine d epend ent) and selective in hibitory (NE-norepinephrine and 5-H T -serotonin d epend ent) influences on cortical neurons. This combination d etermines the regulation of behavior, its goal d irection, its relevance to the actu al tasks. The pred isposition to the goal-oriented selective activity (search activity) requ ires d iscrimination betw een meaningful and meaningless inform ation elicited by the environment. Such d iscrim ination d epend s especially on 5-H T that makes search activity flexible and relevant to the objective reality. Exactly in this sense it is p ossible to speak about the long allele of the serotonin transp orter gene as a gene of happ iness. It is happiness and w ell being based on our search activity.

THE SHORT AN D LON G ALLELE OF 5-HTTLPR IN D EPRESSION AN D AN XIETY
At the same time d epression is characterized by the d ecreased activity of the brain serotonin system and the m ost effective antid epressants are based on serotonin and norepinephrine reuptake inhibition and increase the brain 5-H T and N E. Serotonin is an imp ortant factor in the regulation of the broad spectrum of behavior from feed ing, sexu al and m otor behavior u p to the cognitive activity.
The role of behavioral attitud es in the d evelop ment of d epression w as also show n in our investigations . We have investigated d epressed patients among Russian-speaking new -com ers in Israel using the H am ilton rating scale of d epression and test BASE (Venger et al., 1996)-a projective questionnaire for the evalu ation of d ifferent behavioral attitud es: search activity, stereotyped behavior, panic, and renu nciation of search. In healthy subjects search activity and stereotyped behavior have alw ays p ositive meanings w hile panic and renu nciation of search have negative meaning. In d epressed patients search activity is d ecreased and renunciation of search is increased (Rotenberg, & Cholostoy, 2004). However H amilton rating scale values d o not correlate with behavioral attitud es . It w as no d ifference in the mean values of BASE scales betw een patie nts w ith high (>31) and low (<22.7) scores of H amilton Rating Scale. At the same time the level of d epression w as significantly higher in patients w ith the inverted structure of BASE (panic and / or renu nciation of search is higher than search activity and / o r stereotyp ed behavior) than in p atients w ith the norm al BASE structure. We come to the conclusion that the level of d epression d oes not d etermine the configuration of behavioral attitud es but d ep end s on this configuration. It means that norm alization of b ehavioral attitud es m ay pred ict (or cau se) the d ecrease of d epression in p atients w hile the inversion of behavioral attitud es m ay lead to the exacerbation of d epression. This conclu sion is in agreement w ith some method s of treatment based on the stimu lation of active and constructive behavior. It means that neither d epressive state nor behavior represent the d irect outcome of the level of brain monoam ines but it is a flexible feed back betw een mood , brain m onoamines and behavior.
A meta-analysis of m any investigations of interaction betw een the serotonin transporter gene (5-H TTLPR), stressfu l life events and risk of d ep ression (Risch et al., 2009) have show n that only the number of stressful life events w as significantly associated w ith d ep ression. N o significant association w as fou nd betw een %-H TTLPR genotyp e and d ep ression. It m eans that genotype alone d id not d etermine d epression. There w ere also no d efinite evid ences that serotonin transp orter gene in interaction w ith stressful life events is associated w i th an elevated risk of d epression although such association w as fou nd in some investigations. It means that the S allele of the serotonin transp orter gene is not a gene of d epression. S allele d etermines only a pred isposition to the renunciation of search but this type of behavior m ay represent itself in d ifferent states, not only in d epression. Moreover, subject m ay d isplay an active reaction on stressfu l events even if the level of brain serotonin is initially low ( in another case it w ou ld be impossible to improve the emotional state of d epressed patients throu gh stim ulation of their active behavior. It is also w ell know n that the severity of d epression can sud d enly d rop in some cases w hen p atient is in front of some unexpected and unavoid able events he h as to cope w ith in ord er to help relatives or friend s. In the process of su ch cop ing brain serotonin has a chance to increase).
It w as alread y emphasized that serotonin influences norm al fear (H ariri et al, 2002; H ariri, 2009) that is necessary for the mobilization of bod y resources in the d angerous and ind efinite situ ations. Thu s, it is related to all forms of behavior that includ e search activity (the regulation of behavior in the ind efinite situ ation by mean of the estimation of the all nuances of environment and of the outcome of ow n activity in ord er to m ake this activity more relevant and goal oriented ).
It w as also show n (Ku hnen, & Chiao 2009) that a very sp ecial form of novelty -seeking (search) behavior -financial risk taking -is also d eterm ined by 5-H TTLPR long allele. 5 -H TT LPR S/ S allele carriers (the d om ination of short allele) take 28% less risk than those carrying the S/ L or L/ L alleles of the gene (it means w ith the d om ination of the long allele or at least equal representation of the lon g and short alleles).
Some investigations have show n that effective antid epressants that are increasing the metabolism and activity of serotonin in the brain (SSRI) have a tend ency to activate pred ominantly the left hemisp here (for review see Rotenberg, 2008). I have proposed in this review that it can be explained by the role of the left hemisphere in the outw ard oriented search activity: orientation in environment and selection of d ifferent opportunities of activity accord ing to the d esirable goals. Left hem isp here w ith its ability to d iscriminate relevant and irrelevant inform ation and to focu s on the goal is relevant for this task. Urry et al. (2004) have investigated 84 right hand ed m id d le -aged su bjects. They completed self-reported measures of eud aimonic w ell-being, hed onic w el-being and positive affect prior to EEG registration in a resting cond ition. Authors fou nd that greater left than right superior frontal activation w as associated w ith higher levels of both form s of w ell-being. What seems to be especially interesting in this investigation, that hem isp here specific analysis d ocumented the importance of goal-d irected approach tend encies beyond those captured by approach-related positive affect for eud aimonic but not for hed onic w ell-being. It is possible to suggest that hed onic w ell-being is related to relaxation. Authors em phasized that appropriately engaging sources of appetitive m otivations that are opp osite to the hed onic relaxation (and in m y terms requires active search based on the left hemisp here prefrontal activation) m ay encourage the experience of w ell-being.
In this context it seems im portant to d iscuss the investigation performed by Van d e Vliert (2013). H e investigated the members of d ifferent societies around the w orld , their subjective w ell-being, self-expression, ind ivid ualism and d emocracy, and d ivid ed these societies accord ing to the three types of habitats: a) d em and ingly cold or hot habitats w ith poor monetary resources, b) und emand ing temperate habitats (comfortable climate) in po or or rich areas, and c) demand ingly cold or hot habitats with reach monetary resources. The first cond ition from the author's point of view is threatening becau se the d emand s of the hard clim ate are not satisfied enough in the p oor society. The last cond i tion is a challenging one because althou gh the clim ate is equ ally hard its d emand s can be satisfied . Author found that "although threatening and challenging habitats are both m ore stressful than comforting habitats, su bjective livability in threatening hab itats is w orse than in comforting habitats, w hereas su bjective livability in challenging habitats m ay be exp erienced as even better than in comfortable habitats".
Author comes to the conclusion that the d ifference in m onetary resources by itself d etermines this d ifference in w ell-being betw een the first and the last societies. H ow ever a question rem ains w hy the monetary resources are d ifferent in these societies and w ou ld it be enou gh for w ell-being if the poor society in the d em and ing cond ition w ill be su pported from outsid e by monetary resources? Such opp ortu nity seems to be in contrad iction w ith the proposed d ifference betw een threatening and challenging habitats becau se if money resources w ill come from outsid e w ithout goal-d irected efforts of the society m embers they w ill not create a challenge. And how it happened that in the sim ilar climate one society is poor and another is rich? These questions are ou t of the consid eration of the article.
From my point of view the d emand ing clim ate stimu lated search activity in the members of the last society d ue to some ad d itional historical and cu ltural cond itions (it has to be checked ), and d ue to the high search activity this society achieved its high economical status and w ell-being. It is search activity that m ad e them open-mind ed . Thus econom ical statu s is not the cau se of w ell-being, bu t as w ell as w ell-being by itself, it is an ou tcom e of the relevant reaction on the challenge -of the active search for problem solu tions. When the same d emand s and challenges d o not prod uce search activity (that has to be trained in the society in the process of cultural d evelopment and in the process of ind ivid ual maturation), they became threatening being unavoid able how it happens in the first society. And d ue to the general tend ency to give u p instead of searching for the solution of the problem this society is poor and is characterized by the low level of w ell-being and happiness. In this cond ition the support must be oriented on the stimu lation of search activity.
The und emand ing comfortable clim ate in the intermed iate group pred isp oses su bjects to relaxation and d oes not stimulate search activity for meeting comm on need s of existence. H ow ever it also d oes not cause stress and d oes not su ppress search activity being not threatening, and some groups and members of the society m ay d isplay search activity for intrinsic satisfaction and for grow th need s w hile other group s and members rem ain relaxed . Poor people in these societies often have a pleasure from the calm (easily achieved ) comfort and rich people became satisfied by the realization of their ow n open -mind ed goals.
My hypothesis is confirm ed by d ata that d epression, anxiety, perceived ill health and unhappiness are more prominent in p oor p opu lations resid ing in more d e mand ing clim ate, intermed iately prevalent in pop ulations resid ing in und em and ing clim ate irrespective of income, and least prevalent in rich populations resid ing in d em and ing clim ate. I have alread y emp hasized the role of search activity in health protection in stressful cond itions.
Search activity concept helps also to reconsid er very interesting d ata of Chiao and Blizinsky (2010). These authors found that the societies of East Asia are characterized on the one hand by the prevalence of cultural values of collectivism (opposite to the cultural values of ind ivid ualism in Western societies of Europe and USA) and on the other hand by p revalence of the S allele of the 5-H TTLPR. And qu ite op p osite to w hat is going on in Western societies and w hat w as stressed pr eviou sly in this m anuscript, nations w ith a higher frequency of S allele carriers in East Asia show ed a low prevalence of anxiety and m ood d isord ers.
First of all it confirms that a serotonin transporter gene is not a gene of happ iness. If it w ou ld be a gene of happiness w e w ould have to expect a negative correlation of anxiety and mood d isord ers (states op p osite to w ell-being) not w ith the S allele but w ith L allele. Authors of this investigation believe that in these societies a p rominent collectivism pro tects subjects w ith the d om inating S allele from anxiety and m ood d isord ers. It is correct bu t from m y p oint of view the roots of these relationship s are m ore d eep. They are in the essence of the cultural values of these Far East societies that w ere for ma ny centuries oriented not on changing the outsid e environment (that requires search activity based on the d omination of the left hemispheric style of thinking) bu t on the integration in the environment and in the society, on the d issolution in it and merging w ith it. It d oes not require search activity and d o not prom ote ind ivid u alism. Collectivism prod uces for such integration a comfortable social clim ate com p arable w ith the soft clim ate of natu re. Moreover, in su ch cond itions ind ivid u alism and high ind ivid u al search activity may be even frustrating being in opposition to the general values and attitud es of the society. H ow ever it is possible to su ggest that in special stressful cond itions that requ ire high search activity members of these societies may be less protected . It is confirmed by the greater historical and contemp orary prevalence of d isease-causing pathogens or infectious d iseases in these societies.
My proposition, as I have alread y stressed , is that w hat is supp osed to be a gene of hap p iness and w ell-being (the long allele of 5H TT LPR) is a genetic p red isp osition to search activity and the realization of search activity d eterm ines w ell-being. Of course, search activity may represent itself in the ad ap tive fear and anxiety that are not associated w ith feeling of happ iness and subjective w ell-being. It m ay be one of the reasons w hy even in subjects w ith tw o L versions of the gene more than 30% are not satisfied w ith their life. Subjects w ith one or tw o copies of the short allele (S) of th e serotonin prom oter polymorp hism associated w ith red uced 5-H TT expression and function also may d isplay an increased fear and anxiety related behavior. H ow ever, it is possible to suggest that it is not a normal ad aptive fear that accomp anies active search but a p athological d estructive fear and anxiety combined w ith p anic behavior that accompanies renunciation of search (Rotenberg, Boucsein, 1993). This prop osition may be partly confirmed by d ata (H ariri et al., 2002;Mann 1998) that ind ivid u als w ith short allele exhibit greater am ygd ala neuronal activity in response to fearful stimuli comp ared w ith ind ivid u als that are homozygous for the long allele. Low concentration of the metabolite of serotonin in the cerebrospinal fluid pred icted by short allele is also associated w ith su icid e attem p ts (De Lu ca et al., 2005, 2006.

PARAD OXES OF SUICID ALITY
H ow ever, it is necessary to take into consid eration that these d ata are confirm ed not by all investigators. For instance, Belliver et al., (2000) have found no as sociations betw een S allele of the 5-H TT LPR and su icid e attem p ts. This contrad iction requ ires a com p rehensive d iscussion.
Among patients w ith the history of su icid e attempts S allele frequency w as the highest in those w ho had attemp ted suicid e by violent behavior (.58). Accord ing to 5H TT LPR polymorp hism p atients w ithout su icid al behavior w ere sim ilar to the control subjects. Authors suggest that probably S allele represents a vulnerability factor for suicid al behavior, and especially violent suicid al behavior in affective d isord ers. It is necessary to take into accou nt that d epression can d isp lay itself in a form of passive behavior, total renunciation of search, and in this case a chance for su icid al behavior is not very high. N evertheless it can appear as a final step of the road of giving up that lead s to the finish of life. In this case it w ill be a quiet and not violent behavior. H ow ever, a com bination of d epression w ith a tend ency tow ard s the chaotic (violent) behavior increases the chance for suicid e as an active attempt to escape stressful cond ition, as a protest, as a search for a mysteriou s alternative. Such violent suicid al behavior (attempts) can be consid ered as a m alad aptive misd irected search activity (see Weinberg, 2000) m ixed w ith renu nciation of search that is m ore typ ical for p ure d epression and passivity.
I have d iscussed the role of the misd irected search activity in the p athogenesis of psychotic d isord ers (Rotenberg, 1994) and the violent suicid al behavior is another form of such misd irected and m alad aptive activity. It is a d esperate attem pt to cope w ith u nbearable experience. Regular su icid al attempts occurred among the su bjects w ho continued to feel helplessness and d isplay renunciation of search betw een the episod es of d epression. H ow ever it is rem arkable that som e su bjects a w eek after the su icid al attem p t d isp lay low er levels of hop elessness, d ep ression and su icid al id eation, their p roblem solving ability improves, as if suicid al attempt p arad oxically increased their search activ ity. But it is not surprising if suicid al behavior represents a misd irected search activity. Search activity increases inner resources of bod y and activates brain cathecholamines d oes not m atter w here it is d irected (Rotenberg, 2009).
Accord ing to Weinberg (2000) there are tw o group s of patients w ith su icid al attempts: 1. Those w ho d emonstrate extreme renunciation of search, helplessness and hopelessness and 2. Those w ho d isplay renunciation of search coup led w ith misd irected search activity. Both groups are u nable to use environmental feed back for the red irection of their activity. Special investigations have show n (see Weinberg, 2000) that the relationship s betw een brain monoam ines and suicid ality d iffer from the relationship s betw een brain monoam ines and d epression by itself. Low level of brain 5-H T d oes not lead to su icid e. Among p ersons w ith the suicid al attitud es 5-H T d epletion d ecreases these tend encies w hile suicid e attempts are frequ ently follow ed by increase of N E and 5-H T at least for a short p eriod . It confirm s the statement that suicid al attempts often represent not a d irect outcome of d epression and not a natu ral p art of d ep ression bu t an active, im p u lsive and irrelevant reaction on d ep ression.
It is w ell know n that antid epressants (SSRIs) m ay o n the first step of treatment cause or exacerbate the suicid al attempts (Gold blatt, Shatzberg, 1991). Of course search activity incorp orated in suicid al behavior is not lead ing to the solution of the problem that caused d epression, it is lead ing to a d ead lock and to the further renu nciation of search. Suicid al behavior is a p art of a vicious circle and d oes not allow p atient to turn to the constructive search and exactly for this reason d ifferentiate treatment resistant d epressive patients from the non-resistant.
Thus suicid al behavior often includ es a d estructive search activity. With the exception of d emonstrative suicid e, it is not d irected outsid e and this d estructive search activity cannot have long lasting p ositive perspective. It is reasonable to tak e into consid eration that in some cases su icid e may not d isplay misd irected search activity but only a d efinite and strong w ish not to be, to finish w ith life as a top p oint of renu nciation of search. Probably just in these cases 5-H t in d epressed su bjects w ith suicid e attemp ts is low er than in d epressed patients w ithout suicid e, and the d ifference betw een these tw o versions of suicid e m ay explain the d ifference in the investigations of 5-H T system in d ep ressed su bjects w ith su icid e.
It is a special and very seriou s problem of suicid e attem pts performed by creative ind ivid u als. On the first glance it looks p arad oxically in the context of the present concept because creativity by itself is a pure and highest form of hum an's search activity. H ow ever many creative persons are suffering from bipolar d isord ers, and w hile creativity is associated with hypomanic episod es, d epression, that regularly appears after hyp omania, m ay pred ispose subjects to su icid es, especially those subjects w ho have a regular experience of the extreme activity in hypom ania. The relationship betw een creativity and hypomania m ay be bid irectional becau se both states are based on the sam e brain mechanisms and on the similar brain monoamine systems (DA).
At the same time w hen creative people are out of the state of creative activity they may be pred isposed to d epression not only d ue to their bip olar d isord ers. Creative people are very sensitive to the environment -it is a norm al cond ition for creativity, but it means that they are highly sensitive also to many life events and to emotional experiences that may cause, if negative, a state of helplessness and hopelessness. For the same reasons after finishing creative tasks gifted peop le m ay suffer from the d isapp ointments of achievements and d issociations betw een the imaginative expectations of creative activity and its real outcomes, from p ainful d iscrep ancy betw een their id eal view of the p ossible results of creativity and the real results that are only a pale cop y of id eal. Problems w ith s elf-realization may cause d ep ression and renu nciation of search.
At the present time, the attention of the investigators d isplays a tend ency to shift from searching d irect relationships betw een gene alleles and em otional state of su bjects tow ard more complicated interactions betw een gene alleles, environment (includ ing life stress) and mood . After the consid eration of the results of investigations, De N eve (2011) comes to the conclusion that the u niqu e and single gene of happ iness d oes not persist an d that it is a combination of genes that are influencing the subjective w ell-being in relationships w ith the factors of environment. It seems to be m ore close to the approach prop osed by search activity concept that is also consid ering the interactions betw een the environmental cond itions, behavior and health (mental and physical) (Rotenberg, 2009). The environmental cond itions and especially stressful cond itions require active search, and active search requires a high level of brain serotonin that at least p artly d epend s on the gene alleles. The d eficiency of active search is lead ing to mental and som atic d isord ers, especially in stressfu l cond itions.
Search activity is im portant also in the non -stressful cond itions bu t in these cond itions its level m ay be not so high for ad aptation and for this reason the d eficiency of the serotonin system m ay be less harmful. Grabe et al. (2005) fou nd no ind epend ent associations of genotype w ith mental and physical d istress how ever they found interaction betw een genotype, u nemp loyment and chronic d iseases in fem ales. It w as an interaction betw een short allele of the gene and environment (stress of u nemployment). It can be also related to the d ifference in behavioral attitud es betw een gend ers. Accord ing to our investigation s (see Rotenberg 2009) in men search activity in d em and ing cond itions has a tend ency to be higher than in w omen. I cannot exclud e that this d ifference is related to the process of maturation. Men may became m ore active d ue to the requirem ents of the society and a special training of search activity in the process of maturation. Munato et al. (2008) have also show n a m od est association betw een the 5 H TTLPR short (S) allele and increased negative affect and risk for d epression in the context of environment ad versity. This relationship may be med iated by increased neuroticism. It was also a more robust link betw een S allele and heightened amygd ale activation to emotional stimu li vs. neutral stim uli. Authors p roposed a hyp othesis that the heightened amygd ala activation (especially right amygd ala activation) to the environmental threat may m ed iate the association betw een S allele and increased trait-negative affect as w ell as risk for m ood d isord ers in response to stress.
Of course the d eficiency of the protective search behavior d etermined by the functional w eakness of the brain serotonin system m ay be a key to m ood d isord ers in the threatening environment and the hyp eractivity of the right amygd ala may be a sign of the increased sensitivity to stress.

BRAIN MECHANISMS OF EMOTIONAL SENSITIVITY AND GENES
There are d ata that subjects w ith the d omination of short allele d emons trate the activation of am ygd ala w hile passively view ing pictures w ith emotionally negative content (in comp arison to neutral pictures) and w hile read ing w ord s w ith negative meaning or view ing faces w ith expressions of fear and anger (see Pezaw as et al., 2005). It m ay mean that the short allele is related to the increased em otional sensitivity. H ow ever it m ay have also another explanation.
In subjects w ith the d omination of S allele the gray matter of amygd ala and anterior cingu lated cortex is red u ced and the functional connectivity betw een these system s is d isturbed (see Pezaw as et al., 2005). It may be a reason of the d ecreased ad apt ive ability, of the d eficient response of amygd ala to negative stimu li, of the low fu nctional ability of this system. It may d etermine the vulnerability to d epression. The abovementioned p hysiological activation of the right am ygd ala m ay be an outcome of this low fu nctional ability in the same w ay as the general physiological activation of the right hemisp here is an ou tcome of its functional d eficiency in d epression (Rotenberg, 2004). This explanation seem s to be in a good agreement w ith d ata that subjects w ith the d omination of S allele are pred isposed to d epression.
It is reasonable to take into consid eration also another opportu nity. H ealthy subjects w ith the S allele d isplay a d ecreased activity of d ifferent brain structures (includ ing am ygd al a) w hile performing cognitive tasks w ithou t emotional load in comparison to the control passive relaxed state w ithout particular tasks (Pezaw as et al., 2005).
In this context some d ata of the investigations are especially imp ortant. Thus, it w as show n, that the relatively increased reaction of the amygd ala on the negative emotional stim uli vs. neutral stimuli in subjects w ith high S allele is not a sign of the IN CREASED reaction on the negative em otional cu es (Canli et al., 2005, Canli, Lesch, 2007, Pezaw as et al., 2005. Actu ally it is an ou tcom e of the DECREASED reaction on the neu tral stim u li in comp arison to the fixation rest -relaxed w akefulness w ithout any tasks. Activation d ecreases in am ygd ala across active but em otionally neu tral tasks relative to p assive state i n subjects with S allele in comparison to subjects with L allele. It means that in subjects with high S allele neu tral stim uli d o not evoke any interest and d o not stimu late its investigation that characterizes healthy subjects w ith the long allele and is a sign of spontaneous search activity. In comp arison to these neutral stimuli negative stim uli in subjects w ith the d omination of S allele causes some activation because they need attention and create an unavoid able em otional tension.
At the same time the activation of amygd ala on em otionally neutral tasks that have to be solved accord ing to the task cond itions is even less prominent in subjects w ith d omination of S allele than in the p assive state that causes relaxation in people w ith the d omination of L allele. It means that in this passive state subjects w ith the d omination of S allele are relatively tensed like d epressed p atients, it is a d estructive tension similar to neurotic anxiety, and at the same time they are u nable to m obilize themselves in a constructive w ay even for the solu tion of simple em otionally neutral tasks -also ju st like d epressed patients.
Amygd ala and hippocamp us show ed a gene-environment interaction effect (Pezaw as et al., 2005): activation at rest (comp ared to an active face processing) correlated p ositively w ith life stress in subjects w ith S allele, but negatively in subjects w ith L allele, and in subjects w ith S allele stress caused d epression. It means that activation of these structures d uring rest typ ical in su bjects w ith th e d om inating S alleles reflects the p red isp osition to the m alad ap tive reaction on stress.
Our explanation correspond s also to the negative correlation betw een S allele and social "agreeableness" because such "agreeableness" requires mental flexibility tha t may d isplay search activity.
Thus subjects w ith the d omination of S d isplay the d ecreased activation of some brain structures on the neu tral stimuli instead of the increased activation on the negative stimu li, althou gh their sensitivity to negative information is high. It is confirmed by d ata that it is no d ifference in amygd ala activation betw een the S grou p and L group in response to negativefixation stimuli (Canli et al., 2005). These subjects d isplay a tonic activation of amygd ala in the state of rest combined with its phasic d eactivation by performing tasks that require active behavior. It is very sim ilar to w hat happened w ith physiological brain activation in d epression (see Rotenberg, 2004). It means that am ygd ala in subjects w ith short alleles d isplays a tonic (and functionally irrelevant) activation d ue to the d ecrease of the 5-H T transportation. It is a sign of enhanced em otional sensitivity that d isp lays itself also in the increased reaction of the right insula and putamen not only on negativ e bu t also on neutral w ord s (Canli et al., 2005). Activation of putamen, cau d ate nucleus and thalamus as a reaction on negative stim uli correspond s to the role of these structures in mod u lation of emotional d istress. This d istress is high w hen in stressfu l cond itions search activity is low (Rotenberg, Boucsein, 1993). The activation of brain structures (right am ygd ala) as a reaction on negative vs. neutral w ord s w as alw ays higher in su bjects w ith short alleles tha n in subjects w ith long alleles (Canli et al., 2005). However, it happens because the S group show d ecreased activation in resp onse to neutral stimu li (not d ue to the increased activation to negative stim uli).
Activation of the left hemisphere w as also more prominent in subjects w ith short allele s on positive vs. neutral word s. It need s explanation. Probably positive w ord s are relaxing subjects w ith L allele but are unable to relax subjects w ith S allele?
In the state that has to be a calm state of relaxation subjects w ith the S allele d isplay a more prominent blood flow in amygd ala (Pezaw as et al., 2005). Presu mably it means that a "rest state" in these subjects is a state of the stable inner emotional tension. Such tension has no objective reasons and is d estructive like d istress (See Rotenberg, Boucsein, 1993). This d estructive tension is increased by the negative information but this reaction on the negative information is also not constructive, it d oes not contain search activity, it is not an active d efense. As it w as alread y mentioned , brain activation in the state of rest in these subjects correlates p ositively w ith the life stress and in subjects w ith the d omination of L allele it correlates w ith the life stress negatively. It confirms our proposition that this activation in su bjects w ith S allele reflects the d estru ctive tension w hile in su bjects w ithou t the d om ination of S allele stress cau ses the constructive m obilization that correlates negatively w ith the d estructive activity in the state of rest.
This explanatory proposition is also confirmed by d ata that subjects w ith the d ominating S allele are characterized by ruminations d uring the life stress (Pezaw as et al., 2005). Ru minations are d estructive by them selves.
Subjects w ithout the d om ination of S allele d isplay more physiological tension w hile solving tasks vs. the state of relaxation, and this d ifference is relevant.
Accord ing to Pezaw as et al. (2005) subjects w ith S allele are characterized by the d ecrease of gray m atter in those p arts of the lim bic system that are critical for processing negat ive emotions (especially in am ygd ala and perigenu al cingulated ).
When healthy subjects w ith L allele are d ealing w ith events that can cau se fear they d isplay fight coupling in amygd ala-cingulate circu it as a sign of feed back system that has a task to decrease a negative affect (see Pezawas et al., 2005). Subjects with S allele do not d isplay such coup ling. The amou nt of the fight coupling negatively correlates w ith anxiety. This system is important for the regulation of emotions and is d eficient in subject s w ith the d omination of S allele. Exactly the level of coupling in amygd ala -cingu late circu it, more than the volume of these structures and m ore than their activity, pred icts harm avoid ance as behavioral trait w hat from my point of view is relevant to sea rch activity. Accord ing to Casp i et al. (2010) subjects w ith the 1-2 S alleles are characterized by the increased neuroticism and by the pred isp osition to d epression and in these s ubjects the reaction of am ygd ala on the threat is increased (how ever, as I h ave alread y emphasized , it seems to be a d estructive reaction).
There are d ata (see Caspi et al., 2010) that short allele (S) mod erates the connections betw een a bad insufficient care of the small child (that d etermines the stabilization of the natural tend ency tow ard renunciation of search in a sm all child instead of helping to overcome it) and the d evelopment of d epression and psychosom atic d isord ers. Child ren w ho are characterized by the d omination of the short allele and at the same time have suffered from the bad care in child hood are more sensitive to negative experiences and are pred isposed to the bad self-regulation. In stressfu l cond itions they are m ore anxious. It w as su ggested that a short allele of 5H TTLPR is a genetic p red isp osition to neu roti cism , how ever this pred isp osition d etermines the d evelopment of the d isease only in the cond ition of stress. From m y p oint of view it is a real p red isp osition tow ard s renu nciation of search.
Serotonin is very important for the med iation of connections betw een amygd ala and med ial prefrontal cortex. The latter is resp onsible for the goal d irected behavior that contains search activity and limits reactivity of the amygd ala (because the constructive search activity blocks the d estructive emotional tension). In su bjects w ith the d omination of S allele and w ith the d eficiency of 5-H T transportation the functional activity of this system is d isturbed and the gray matter of amygd ala and med ial prefrontal cortex is d ecreased . The general sensitivity to stressful even ts is increased and it is d ifficu lt for the subject to sw itch attention from these fru strating events although this attention d oes not d etermine the constructive protective behavior.
It w as show n (Sp inelli et al., 2007) that you ng m onkeys w ith the d om inati on of S allele d isplay less prominent active coping and protest being sep arated from the mother. At the same time they d isplay m ore prominent anxiety, agitation, stereotype behavior, increased H PA and ACTH reactions on stress, and it is opp osite to the con structive search activity and correspond s to renu nciation of search. The authors conclud ed that accord ing to the resu lts of all investigations on hu m ans and on anim als it is unreasonable to search for a sp ecial genetic pred isposition to the mental d isord ers and it is more reasonable to search for the influence of d ifferent genes on the vulnerability to stressfu l events and for the relationships betw een genetic p articu larity and environment factors as a real reason of mental d isord ers. It is a lso in agreement w ith the search activity concept: the renu nciation of search is especially d angerou s and vulnerable in stressful cond itions that require search activity for coping and survival. Caspi et al. (2003) have show n that subjects w ith the short allele d em onstrate m ore p rom inent d ep ression in stressfu l cond itions than su bjects w ith long allele.
Accord ing to Fox et al. (2009) allele variation in the p rom oter region of the serotonin transp orter gene (5-H TTLPR) is associated w ith d ifferential biases for p ositive and negative affective p ictu res. Ind ivid u als hom ozygou s for tw o L (LL) version show ed a m arked bias to selectively process p ositive affective m aterial alongsid e selective avoid ance of negative affective m aterial. This potentially protective p attern w as absent am ong ind ivid uals carrying the S allele of gene (S or SL combination) w ho d isp layed an orientation tow ard s negative affective m aterial and avoid ance of positive stimu li. It w as observed w hen affective m aterial (pictures w ith p ositive and negative valence) w as presented d uring 500 m sec., thus it w as the first reaction on the affective stimuli, performed im m ed iately after its holistic grasping and before its successful integration. It means that ind ivid u als w ith the d omination of S allele a re initially pred isp osed tow ard s fixation on negative affective inform ation. It is a sign of high emotional sensitivity probably combined w ith the d eficiency of protective strategy that includ es search activity.
H ow ever, some investigations contain on the first glance opposite results. Beevers et al. (2011) investigated the attention to positive and negative facial expressions in su bjects w ith the long and short alleles. Those w ith the S alleles and w ith LG (long allele w ith guanine that is close to S allele) d emonstrated the preference of the gaze tow ard the p ositive stimu li. Subjects w ith LA (long allele w ith ad enine that d etermines the m ost prominent serotonin activity) d o not d em onstrate preferences to any emotional stimuli. H ow ever it is necessary to take into consid eration that in this investigation w as u sed a m ore long p eriod of the presentation of affective stimuli -5 sec. or even longer w hile in the investigation of Fox et al. it w as 500 msec. Beevers et al. propose that in the later stages of info rm ation processing highly sensitive subjects w ith S allele, w ho are u nable to integrate the negative affective information prefer to orient their attention on p ositive im ages. It looks out as if subjects w ith the S and LG alleles w ere looking for any opp or tu nity to red uce their emotional tension caused by negative stimuli. For the subjects w ith LA allele it is not necessary because their high brain mechanisms of integration the potentially threatening inform ation (right frontal lobe, see Rotenberg 2007) are more flexible and more active. Beevers and al. (2011) mentioned that w hen healthy peop le are instructed to regulate their emotions volitionally they also view negative em otional im ages less often and positive images m ore often. It means that they d irect their attention on positive im ages. It is imp ortant that subjects w ith the d omination of S/ LG allele view ed neutral stim uli in a similar fashion to their view ing of sad and fearfu l facial expressions. Subjects w ith S/ LG allele either actively d irected atten tion tow ard happy faces (rather than simply avoid ing negative stimuli) or they view ed neutral faces as negative one like it happened in high trait and state anxiety.
It is necessary to take into consid eration that the concentration on the positive stim uli and attempts to avoid negative stimuli not on the initial stage of perception but d u ring the all processes of perception is sim ilar to the perceptu al psychological d efense and is not constructive in the real life because it d eterm ines the "blind ness" to a real d anger. Such perceptual d efense means that subject cannot ad opt him self to the negative experience, to integrate it in his mental life. In combination w ith a high emotional sensitivity that w as alread y mentioned (and that d isplay itself also in the just cited investigation , Beevers et al., 2011) it d eterm ines attemp ts of su bjects w ith the d ominating S allele to avoid and ignore im p ortant inform ation that cau ses em otional tension instead of cop ing w ith it. Probably these subjects like schizophrenic patients have a tend ency to perceive even neutral facial expressions as negative and d angerou s (see Rotenberg, 2011) and try to concentrate their attention on happy faces. In subjects w ith S/ LG allele the functioning of the serotoninergic system is d ecreased (w hat d etermines low search activity) and is accomp anied by the increased sensitivity to negative em otional stim u li, w hile su bjects w ith LA allele related to the increase of the transcrip tional 5H T activity are more protected from stressful events.

CON CLUSION
From the all abovem entioned d ata it is p ossible to m ake the follow ing conclu sion. The socalled genes of happiness and w ell-being actu ally represent the genetic pred isposition to search activity that is stim ulated by the new and stressful e vents of the environment. Search activity not only protects m ental and somatic health bu t also brings subject an exciting feeling of overcoming obstacles, of find ing new solutions, of achieving goals, of creating new reality and for all these reasons it is subjectively perceived as w ell-being or even happ iness.