a groundbreaking paradigm shift , the discovery of noncoding rnas ( ncrnas ) , established the conventional one gene , one protein  model to be an oversimplified view of gene regulation . numerous ncrna classes are now implicated in central nervous system ( cns ) functions ; micrornas ( mirnas ) , natural antisense transcripts ( nats ) and long intergenic rnas ( lincrnas ) all have reported regulatory activities in the brain . while pleiotropic ncrnas , including mirnas , can target large numbers of genes and signaling pathways simultaneously , there are also ncrnas , such as nats , which hybridize to a limited and precise subset of candidates . growing evidence indicates that distinct neuronal ncrna mechanisms , particularly mirnas , likely influence the development of psychiatric disease . here we review the role of mirnas in the neurobehavioral deficits of cns disorders and also discuss the reported contributions of other ncrna classes . mirnas have recently emerged as a global regulator of gene expression and , ultimately , effector of synaptic physiology . these mirnas function by several mechanisms , including ribosomal rna modifications , repression of mrna expression by rna interference , alternative splicing , and regulatory mechanisms mediated by rna - rna interactions . the processing from a primary ( pri ) transcript to precursor ( pre ) and mature mirna in the brain requires the standard mirna biogenesis machinery , including drosha , dicer , dgcr8 , and argonaute ( ago ) proteins . functional knockdown of dicer , which processes the pre - mirna to its mature transcript , leads to reduced neuronal size and branching as well as aberrant axonal pathfinding . correspondingly , mice with genetic knockout of the pri - mirna processing protein dgcr8 display a loss of synaptic connectivity and reduced number and size of dendritic spines . at the behavioral level , these mice display impaired spatial working memory - dependent tasks . interestingly , it has been shown that mirnas are formed in part by processing of pre - mirnas locally within dendritic spines . furthermore , synaptic stimulation leads to local processing of pre - mirnas in proximity to the synapse ; a cohort of mirnas are localized within the synapse , including mir-219 - 5p , mir-124 , mir-134 , mir-138 , and mir-125b . these mirnas directly impact learning and memory behaviors , neurotransmission , neurogenesis among other functions   and their disruption contribute to psychiatric impairments . the transition from neural stem cells ( nscs ) to neural progenitors and ultimately to fully differentiated neurons is highly regulated by a complex interaction of mirnas and other factors . in general , let-7 , mir-124   and mir-9 it is typically held that mir-134   and mir-25   induce the proliferation and/or inhibit the differentiation of nscs and neural progenitors . in parallel , mir-137 both decreases   and increases   nsc proliferation , either enhancing or opposing neuronal maturation . there is an intricate overlap and feedback occurring between these key mirnas , mediated in part by their target genes . adult neurogenesis is reportedly decreased in neurodegenerative disease   and depression , and is modulated by antidepressant therapeutics . thus , the following discussions regarding mirna pathways in psychiatric disorders ( outlined in table 1 ) may involve neurons derived at all stages of brain maturity . the copy number variant ( cnv ) at 22q11.2 , resulting in digeorge syndrome , is the most common rare variant identified in schizophrenia , occurring in approximately one percent of patients . many children with 22q11.2 deletion syndrome have developmental delays and learning disabilities , with a substantially elevated risk of developing schizophrenia ( 30% ) . though the 22q11.2 region contains 30 to 40 genes , many have not been well characterized ; one notable gene is digeorge syndrome critical region gene 8 ( dgcr8 ) , an essential contributor to microrna biogenesis . microdeletion of 22q11.2 in mice results in the downregulation of a cluster of mirnas with corresponding changes in cognitive and behavioral functions . of the common genetic variants enriched in patients with schizophrenia , there is a well - established signal at mir-137 and several of its target genes . schizophrenia patients with a mir-137 risk allele exhibit greater symptom severity , significantly altered functional connectivity , reduced white matter integrity , smaller hippocampi and larger lateral ventricles . functionally validated targets of mir-137 include such schizophrenia risk genes as cacna1c , tcf4   and znf804a , while additional putative targets include erbb4 , gabra1 , grin2a , grm5 , gsk3b , nrg2 , and htr2c . overexpression of mir-137 in a human nsc line identified direct and indirect mir-137 targets in neural cells . while direct mir-137 targets were enriched for transcription factors and cell cycle genes , indirect targets included pathways enriched in schizophrenia genome wide association studies , particularly major histocompatibility complex , synapses , fmrp interacting rnas and calcium channels . more recently , the largest study of common variance identified 108 regions significantly associated with schizophrenia , including significant hits at mir-137 and mir-548 . post - mortem profiling of mirna expression in the prefrontal cortex of schizophrenia patients identified a global increase in mirna expression compared to control populations . more specifically , although the mature and pre - mirna species were increased ( particularly of mir-181b and mir-26b ) , there was no significant difference in transcription of the source pri - mirna . these results suggest that the changes were due to increased mirna biogenesis rather than altered mirna transcription . the authors further observed upregulated expression of drosha and dgcr8 , both of which are involved in pri - mirna processing , and speculate this is the ultimate cause of aberrant mirna levels . additionally , human analyses have started to reveal a profile signature of mirna dysregulation in peripheral tissues such as plasma and serum of schizophrenia patients . intriguingly , plasma levels of mir-181b ( discussed above ) were found to predict response to antipsychotic treatment ; correspondingly , mir-30e has also been postulated as a plasma biomarker of schizophrenia . nmda - r signaling , one of the most consistently implicated pathways in schizophrenia , is strongly controlled by mir-219 . notably , mir-219 is the most enriched mirna in the human synapse , the most downregulated in cortical synaptosomes of schizophrenia patients , and was dysregulated in cortical tissue from two patient cohorts . moreover , neuronal inhibition of mir-219 - 5p in mice significantly altered the precipitation of schizophrenia behavior by nmda - r antagonists . taken together , mir-219 - 5p actively mediates synaptic functions and the development of psychiatric phenotypes . nmda - r also regulates mir-132 , which is implicated in learning and memory functions , long - term potentiation   and neurotransmission . mir-132 expression is repressed in mice with genetic disruption of the enzyme which produces the nmda - r co - agonist d - serine , and these d - serine deficient mice recapitulate some of the neurobehavioral and cognitive impairments presented in patients with schizophrenia . expression of mir-132 was dysregulated in human cortical tissue from two schizophrenia datasets but those expression changes were in opposite directions ; it remains possible that mir-132 is disrupted in specific neuronal cell types or distinct subcellular regions of neurons in schizophrenia . interestingly , the nmda - r regulated transcripts mir-132 and mir-219 - 5p ( discussed above )   regulate circadian rhythm , which is frequently disrupted in schizophrenia and other psychiatric disorders . in addition , a subset of other mirnas also reportedly regulate circadian functions , including mirs  279 , 142 - 3p , 185 , 138 , let-7b , 125a , 206 and 182 . indeed , mirna regulators of nmda - r signaling and circadian rhythm could yield new therapeutic targets for treatment of neurobehavioral deficits . mirna expression is responsive to current therapeutics administered for bipolar disorder , which is known to share overlapping genetic links with schizophrenia . in rats treated with either lithium or valproate , there are a cohort of mirnas altered in the hippocampus , including let-7b , let-7c , mir-128a , mir-24a , mir-30c , mir-34a , mir-221 and mir-144 . valproate and lithium significantly modulate brain - derived neurotrophic factor ( bdnf ) levels , a critical regulator of neuronal homeostasis , which is itself regulated by both short and long ncrnas , such as mir-124a . notably , mir-124a is linked to depression - related behaviors , as discussed in the section below . as more post - mortem datasets become publicly available , we believe that groups of consistently altered transcripts in schizophrenia and bipolar disorder will emerge and potentially converge . combining multimodal snp and exome sequencing genotype information with rna and mirna expression datasets will facilitate mirna - mrna correlations . arguably , some of the more persistent mirna associations in schizophrenia to date implicate mir-137 , mir-181b , and mir-219 - 5p ( table 1 ) . there is accumulating evidence for significant contribution of mirna mechanisms in mood disorders such as depression . in the prefrontal cortex of depressed subjects who had died by suicide , 21 mirnas were significantly down - regulated in the major depressive disorder ( mdd ) group . more mirnas were down - regulated than upregulated , implying a global down - regulation of mirna levels in mdd . furthermore , almost half of the down - regulated mirnas were transcribed by the same pri - mirna gene transcripts ( mir-142 - 5p and 142 - 3p ; mir-494 , 376a * , 496 , and 369 - 3p ; mir-23b , 27b and 24 - 1 * ; mir-34b * and 34c ; mir-17 * and 20a ) or found within the same chromosomal region ( mir-424 and 20b at xq26.2 - 3 , 377 kb apart ; mir-142 and 301a at 17q22 , 820 kb apart ; mir-324 - 5p and 497 at 17p13.1 , 205 kb apart ) , suggesting that the down - regulated mirna expression may be due to decreased transcription . in addition , a set of 29 mirnas formed an inter - connected network in the mdd group : let-7b , mir-132 , 181b , 338 - 3p , 486 - 5p , and 650 were hubs  . a recent study of genotyping polymorphisms from three mirna processing genes ( dgcr8 , ago1 , and gemin4 ) found that dgcr8 rs3757 was associated with increased risk of suicidal tendency and improvement response to antidepressant treatment , whereas ago1 rs636832 showed decreased risk of suicidal tendency , suicidal behavior , and recurrence . thus , polymorphisms in mirna processing genes may influence depression risk and treatment . molecular targets of anti - depressants frequently engage the transporters of serotonin , a monoamine neurotransmitter . mirnas regulate the serotonin transporter ( sert ) and its response to serotonin reuptake inhibitor ( ssri ) therapeutics . specifically , ssri antidepressant fluoxetine ( prozac ) treatment in mice induces expression of mir-16 while repressing the mir-16 target sert . another sert associated mirna , mir-135 , was found to control the onset of co - existing depression and anxiety symptoms in mice   as well as the response to anti - depressant treatment . because of limited studies in depressed patients , it is difficult to pinpoint specific mirnas consistently implicated in the pathogenesis of depression ; nevertheless , mirnas that influence bdnf , including mir-132 and mir-34 , and neuroinflammation , such as the let-7 family , may be highly relevant ( table 1 ) . intriguingly , mir-124a repression of bdnf provokes depression - related behaviors   and significantly mediates neurogenesis . future studies could investigate if current anti - depressant therapeutics signal through mir-124a or other disease - associated mirnas to enhance adult hippocampal neurogenesis . the link between ncrnas and stress , anxiety , or fear related responses opens new avenues for therapeutic intervention . while a range of genetic associations have been loosely implicated in post - traumatic stress disorder ( ptsd ) , epigenetic factors likely play a defining role in disease progression . a panel of disrupted mirnas in the blood of military veterans with active ptsd symptoms have been identified ; these ptsd - associated mirnas were significantly associated with immunological pathways , suggestive of their pathogenic mechanisms in the disorder . indeed , abnormal systemic immune responses are routinely reported in stress - related conditions , consistent with its regulation by the ptsd - linked mirnas . intriguingly , a few of the mirna transcripts altered in the veterans suffering from ptsd , including mir-19b and mir-223 , were also perturbed in the serum and amygdala of a ptsd animal model . stress and anxiety , however , are not unique behaviors to ptsd and are provoked through many distinct triggers . overexpression of mir-34c in the central amygdala elicited an anxiolytic - like effect in mice stressed through acute restraint ; furthermore , mir-34c directly targets a key mediator of stress responses , the corticotropin releasing factor receptor type 1 ( crfr1 ) gene . notably , mir-34a was recently reported to regulate fear related responses through notch signaling in mice . although mir-34a did nt alter anxiety - related parameters in the same manner as mir-34c , it is possible that the mir-34 family is central in behavioral manifestations . in addition to the above mentioned mirnas , mirs - 608 , 124a , 132 , 330 - 3p , and 16 are also implicated in anxiety phenotypes through genetic associations or in vivo analyses . specifically , mir-124 is linked to both anxiety and stress related behaviors through glucocorticoid and corticosteroid signaling , respectively . moreover , ablation of the mirna biogenesis enzyme dicer in the central amygdala of mice provoked the onset of anxiety - like symptoms . mice with dicer knockout specifically in dopaminoceptive neurons also exhibit behavioral changes , including ataxia as well as front and hind limb clasping . human genetic linkage studies and animal models also revealed mirna pathways in panic or fear responses . at least four mirnas have single- nucleotide polymorphisms ( snps ) in mirna sequences located within panic disorder associated genes , including mir-22 , mir-138 - 2 , mir-148a , and mir-488 . furthermore , mir-128 expression is increased with the formation of fear - extinction memory in mice , which is the re - conditioning of the memory to overcome established fear behaviors . an individual s ability to cope with there is contrasting mirna expression between rats who developed learned helpless ( lh ) , a behavior that resembles stress - induced depression , compared to rats who did not develop depression ( non - learned helpless [ nlh ] ) in spite of receiving similar inescapable shocks . one set of mirnas showed large , significant , and consistent down - regulation in the frontal cortex of nlh rats compared to a blunted response in lh rats ( mir-96 , mir-141 , mir-182 , mir-183 , mir-183 * , mir-198 , mir-200a , mir-200a * , mir-200b , mir-200b * , mir-200c , and mir-429 ) . these synaptically enriched mirnas are encoded at a few shared polycistronic loci , suggesting coordinated control of their transcription , and they share 5-seed motifs which indicate similar or overlapping sets of target mrnas . interestingly , half of this set are predicted to hit creb1 as a target , and binding sites for creb lie upstream of mir-96 , mir-182 , mir-183 , mir-200a , mir-200b , mir-200c , mir-220a * , and mir-200b*. this suggests that a feedback loop arrangement may also exist between creb and creb - stimulated mirnas and target genes . because these mirnas are down regulated in nlh rats , but not lh rats , this can be interpreted as a homeostatic response intended to minimize repressive effects on creb1 . although more studies are needed to identify a list of mirnas associated with stress , anxiety and fear , some putative candidates are emerging ( table 1 ) . as discussed previously , mir19b and mir-223 were dysregulated in human and animal models of ptsd   and should be evaluated further for therapeutic targeting in trauma - induced stress . notably , these two transcripts share over 80 bioinformatic mrna targets through targetscan prediction . additionally , the mir-34 family may exhibit an overlapping role in anxiety and fear responses . overall , replication studies in human and animals will further define persistent mirna mechanisms in these neurobehavioral deficits . the copy number variant ( cnv ) at 22q11.2 , resulting in digeorge syndrome , is the most common rare variant identified in schizophrenia , occurring in approximately one percent of patients . many children with 22q11.2 deletion syndrome have developmental delays and learning disabilities , with a substantially elevated risk of developing schizophrenia ( 30% ) . though the 22q11.2 region contains 30 to 40 genes , many have not been well characterized ; one notable gene is digeorge syndrome critical region gene 8 ( dgcr8 ) , an essential contributor to microrna biogenesis . microdeletion of 22q11.2 in mice results in the downregulation of a cluster of mirnas with corresponding changes in cognitive and behavioral functions . of the common genetic variants enriched in patients with schizophrenia , there is a well - established signal at mir-137 and several of its target genes . schizophrenia patients with a mir-137 risk allele exhibit greater symptom severity , significantly altered functional connectivity , reduced white matter integrity , smaller hippocampi and larger lateral ventricles . functionally validated targets of mir-137 include such schizophrenia risk genes as cacna1c , tcf4   and znf804a , while additional putative targets include erbb4 , gabra1 , grin2a , grm5 , gsk3b , nrg2 , and htr2c . overexpression of mir-137 in a human nsc line identified direct and indirect mir-137 targets in neural cells . while direct mir-137 targets were enriched for transcription factors and cell cycle genes , indirect targets included pathways enriched in schizophrenia genome wide association studies , particularly major histocompatibility complex , synapses , fmrp interacting rnas and calcium channels . more recently , the largest study of common variance identified 108 regions significantly associated with schizophrenia , including significant hits at mir-137 and mir-548 . post - mortem profiling of mirna expression in the prefrontal cortex of schizophrenia patients identified a global increase in mirna expression compared to control populations . more specifically , although the mature and pre - mirna species were increased ( particularly of mir-181b and mir-26b ) , there was no significant difference in transcription of the source pri - mirna . these results suggest that the changes were due to increased mirna biogenesis rather than altered mirna transcription . the authors further observed upregulated expression of drosha and dgcr8 , both of which are involved in pri - mirna processing , and speculate this is the ultimate cause of aberrant mirna levels . additionally , human analyses have started to reveal a profile signature of mirna dysregulation in peripheral tissues such as plasma and serum of schizophrenia patients . intriguingly , plasma levels of mir-181b ( discussed above ) were found to predict response to antipsychotic treatment ; correspondingly , mir-30e has also been postulated as a plasma biomarker of schizophrenia . nmda - r signaling , one of the most consistently implicated pathways in schizophrenia , is strongly controlled by mir-219 . notably , mir-219 is the most enriched mirna in the human synapse , the most downregulated in cortical synaptosomes of schizophrenia patients , and was dysregulated in cortical tissue from two patient cohorts . moreover , neuronal inhibition of mir-219 - 5p in mice significantly altered the precipitation of schizophrenia behavior by nmda - r antagonists . taken together , mir-219 - 5p actively mediates synaptic functions and the development of psychiatric phenotypes . nmda - r also regulates mir-132 , which is implicated in learning and memory functions , long - term potentiation   and neurotransmission . mir-132 expression is repressed in mice with genetic disruption of the enzyme which produces the nmda - r co - agonist d - serine , and these d - serine deficient mice recapitulate some of the neurobehavioral and cognitive impairments presented in patients with schizophrenia . expression of mir-132 was dysregulated in human cortical tissue from two schizophrenia datasets but those expression changes were in opposite directions ; it remains possible that mir-132 is disrupted in specific neuronal cell types or distinct subcellular regions of neurons in schizophrenia . interestingly , the nmda - r regulated transcripts mir-132 and mir-219 - 5p ( discussed above )   regulate circadian rhythm , which is frequently disrupted in schizophrenia and other psychiatric disorders . in addition , a subset of other mirnas also reportedly regulate circadian functions , including mirs  279 , 142 - 3p , 185 , 138 , let-7b , 125a , 206 and 182 . indeed , mirna regulators of nmda - r signaling and circadian rhythm could yield new therapeutic targets for treatment of neurobehavioral deficits . mirna expression is responsive to current therapeutics administered for bipolar disorder , which is known to share overlapping genetic links with schizophrenia . in rats treated with either lithium or valproate , there are a cohort of mirnas altered in the hippocampus , including let-7b , let-7c , mir-128a , mir-24a , mir-30c , mir-34a , mir-221 and mir-144 . valproate and lithium significantly modulate brain - derived neurotrophic factor ( bdnf ) levels , a critical regulator of neuronal homeostasis , which is itself regulated by both short and long ncrnas , such as mir-124a . notably , mir-124a is linked to depression - related behaviors , as discussed in the section below . as more post - mortem datasets become publicly available , we believe that groups of consistently altered transcripts in schizophrenia and bipolar disorder will emerge and potentially converge . combining multimodal snp and exome sequencing genotype information with rna and mirna expression datasets will facilitate mirna - mrna correlations . arguably , some of the more persistent mirna associations in schizophrenia to date implicate mir-137 , mir-181b , and mir-219 - 5p ( table 1 ) . there is accumulating evidence for significant contribution of mirna mechanisms in mood disorders such as depression . in the prefrontal cortex of depressed subjects who had died by suicide , 21 mirnas were significantly down - regulated in the major depressive disorder ( mdd ) group . more mirnas were down - regulated than upregulated , implying a global down - regulation of mirna levels in mdd . furthermore , almost half of the down - regulated mirnas were transcribed by the same pri - mirna gene transcripts ( mir-142 - 5p and 142 - 3p ; mir-494 , 376a * , 496 , and 369 - 3p ; mir-23b , 27b and 24 - 1 * ; mir-34b * and 34c ; mir-17 * and 20a ) or found within the same chromosomal region ( mir-424 and 20b at xq26.2 - 3 , 377 kb apart ; mir-142 and 301a at 17q22 , 820 kb apart ; mir-324 - 5p and 497 at 17p13.1 , 205 kb apart ) , suggesting that the down - regulated mirna expression may be due to decreased transcription . in addition , a set of 29 mirnas formed an inter - connected network in the mdd group : let-7b , mir-132 , 181b , 338 - 3p , 486 - 5p , and 650 were hubs  . a recent study of genotyping polymorphisms from three mirna processing genes ( dgcr8 , ago1 , and gemin4 ) found that dgcr8 rs3757 was associated with increased risk of suicidal tendency and improvement response to antidepressant treatment , whereas ago1 rs636832 showed decreased risk of suicidal tendency , suicidal behavior , and recurrence . thus , polymorphisms in mirna processing genes may influence depression risk and treatment . molecular targets of anti - depressants frequently engage the transporters of serotonin , a monoamine neurotransmitter . mirnas regulate the serotonin transporter ( sert ) and its response to serotonin reuptake inhibitor ( ssri ) therapeutics . specifically , ssri antidepressant fluoxetine ( prozac ) treatment in mice induces expression of mir-16 while repressing the mir-16 target sert . another sert associated mirna , mir-135 , was found to control the onset of co - existing depression and anxiety symptoms in mice   as well as the response to anti - depressant treatment . because of limited studies in depressed patients , it is difficult to pinpoint specific mirnas consistently implicated in the pathogenesis of depression ; nevertheless , mirnas that influence bdnf , including mir-132 and mir-34 , and neuroinflammation , such as the let-7 family , may be highly relevant ( table 1 ) . intriguingly , future studies could investigate if current anti - depressant therapeutics signal through mir-124a or other disease - associated mirnas to enhance adult hippocampal neurogenesis . the link between ncrnas and stress , anxiety , or fear related responses opens new avenues for therapeutic intervention . while a range of genetic associations have been loosely implicated in post - traumatic stress disorder ( ptsd ) , epigenetic factors likely play a defining role in disease progression . a panel of disrupted mirnas in the blood of military veterans with active ptsd symptoms have been identified ; these ptsd - associated mirnas were significantly associated with immunological pathways , suggestive of their pathogenic mechanisms in the disorder . indeed , abnormal systemic immune responses are routinely reported in stress - related conditions , consistent with its regulation by the ptsd - linked mirnas . intriguingly , a few of the mirna transcripts altered in the veterans suffering from ptsd , including mir-19b and mir-223 , were also perturbed in the serum and amygdala of a ptsd animal model . stress and anxiety , however , are not unique behaviors to ptsd and are provoked through many distinct triggers . overexpression of mir-34c in the central amygdala elicited an anxiolytic - like effect in mice stressed through acute restraint ; furthermore , mir-34c directly targets a key mediator of stress responses , the corticotropin releasing factor receptor type 1 ( crfr1 ) gene . notably , mir-34a was recently reported to regulate fear related responses through notch signaling in mice . although mir-34a did nt alter anxiety - related parameters in the same manner as mir-34c , it is possible that the mir-34 family is central in behavioral manifestations . in addition to the above mentioned mirnas , mirs - 608 , 124a , 132 , 330 - 3p , and 16 are also implicated in anxiety phenotypes through genetic associations or in vivo analyses . specifically , mir-124 is linked to both anxiety and stress related behaviors through glucocorticoid and corticosteroid signaling , respectively . moreover , ablation of the mirna biogenesis enzyme dicer in the central amygdala of mice provoked the onset of anxiety - like symptoms . mice with dicer knockout specifically in dopaminoceptive neurons also exhibit behavioral changes , including ataxia as well as front and hind limb clasping . human genetic linkage studies and animal models also revealed mirna pathways in panic or fear responses . at least four mirnas have single- nucleotide polymorphisms ( snps ) in mirna sequences located within panic disorder associated genes , including mir-22 , mir-138 - 2 , mir-148a , and mir-488 . furthermore , mir-128 expression is increased with the formation of fear - extinction memory in mice , which is the re - conditioning of the memory to overcome established fear behaviors . an individual s ability to cope with there is contrasting mirna expression between rats who developed learned helpless ( lh ) , a behavior that resembles stress - induced depression , compared to rats who did not develop depression ( non - learned helpless [ nlh ] ) in spite of receiving similar inescapable shocks . one set of mirnas showed large , significant , and consistent down - regulation in the frontal cortex of nlh rats compared to a blunted response in lh rats ( mir-96 , mir-141 , mir-182 , mir-183 , mir-183 * , mir-198 , mir-200a , mir-200a * , mir-200b , mir-200b * , mir-200c , and mir-429 ) . these synaptically enriched mirnas are encoded at a few shared polycistronic loci , suggesting coordinated control of their transcription , and they share 5-seed motifs which indicate similar or overlapping sets of target mrnas . interestingly , half of this set are predicted to hit creb1 as a target , and binding sites for creb lie upstream of mir-96 , mir-182 , mir-183 , mir-200a , mir-200b , mir-200c , mir-220a * , and mir-200b*. this suggests that a feedback loop arrangement may also exist between creb and creb - stimulated mirnas and target genes . because these mirnas are down regulated in nlh rats , but not lh rats , this can be interpreted as a homeostatic response intended to minimize repressive effects on creb1 . although more studies are needed to identify a list of mirnas associated with stress , anxiety and fear , some putative candidates are emerging ( table 1 ) . as discussed previously , mir19b and mir-223 were dysregulated in human and animal models of ptsd   and should be evaluated further for therapeutic targeting in trauma - induced stress . notably , these two transcripts share over 80 bioinformatic mrna targets through targetscan prediction . additionally , the mir-34 family may exhibit an overlapping role in anxiety and fear responses . overall , replication studies in human and animals will further define persistent mirna mechanisms in these neurobehavioral deficits . although mirnas are arguably the most extensively characterized class of ncrna in neurons , long ncrnas ( lncrna ) are increasingly implicated in cns functions . long ncrnas acts as mirna sponges and can bind proteins and rnas that regulate transcriptional changes and epigenetic modifications of chromatin . indeed , these transcripts regulate basic neuronal biology as well as genes with strong disease - association . bc1 , one of the first lncrna transcripts characterized in the brain , is now known to modulate metabotropic receptor signaling . select members of the nat class of ncrnas in the brain are functional and modulate expression of their sense partner ; nats are endogenously transcribed and exhibit at least partial sequence complimentarity to protein - coding genes , ranging from short to long in nucleotide length . an emerging area of investigation indicates that long and short neuronal ncrnas are co - regulatory , which is discussed more throughout the following sections . for example , the bace1 gene linked to psychiatric and cognitive deficits in alzheimer s disease ( ad ) ] is reportedly modulated by a network of competitive ncrna interactions . more specifically , it was shown that mir-485 - 5p binding sites in bace1 are masked through a long antisense transcript , bace1-as . evidence demonstrates that lncrnas participate in neural plasticity , supported by the expression of a large number of these transcripts in dendrites . in addition , a genome - wide analysis show that lncrnas are modulated by neuronal activity in human brain . reports suggest that fine - tuned regulatory control of the embryonic brain by these transcripts is required for development of mature cns functions . mouse knockout studies involving long - intergenic ncrnas ( lincrnas ) found that loss of function for linc brn1b results in a reduction of cerebral cortex progenitor cells and abnormal cortical lamination amongst other pathologies . furthermore , a subset of lincrnas bind mirnas and inhibit their functions ( i.e. mirna sponge ) , which can reportedly disrupt brain development . circular ncrnas ( circrna ) were also recently reported to function as mirna sponges in neurons . for example , a circrna was found to have multiple mirna binding sites , including for mir-7 , and both were co - expressed in neocortical and hippocampal neurons . these studies further indicate the importance of interactions between ncrnas in the brain and the need to uncover their epigenetic networks . neurotrophins , which play a key role in maintaining homeostatic activity in the cns , reportedly respond to lncrna signaling . for example , the neurotrophin bdnf has sequence complementarity with a conserved nat , termed bdnf - as . functionally , bdnf - as was reported to modulate neuronal growth in vitro and in vivo 
 . the sequence complementarity of this noncoding transcript appears to extend into the 3 untranslated region ( 3utr ) of bdnf , which contains regulatory mirna binding sites such as mir-124a . mir-124 , as discussed in previous sections , modulates depression and related neurobehavioral deficits ; it is possible that the bdnf - as partly functions by preventing mir-124 from binding to bdnf . for example , an endogenous noncoding antisense transcript to the htt gene ( httas ) functionally regulates htt expression , which is the primary genetic aberration in hd and associated cognitive and neurobehavioral pathology . genetic variations in the disrupted in schizophrenia 1 ( disc1 ) gene are consistently linked with schizophrenia - associated behaviors . a recent report suggests the lncrna gomafu mediates disc1 splicing events , resulting in splice variants linked to schizophrenia . gomafu , is implicated in neural development   and is downregulated in cortical tissue of schizophrenia patients and in activated human neuronal cells . several groups have reported genetic association of disc2 with schizophrenia as well as other psychiatric disorders ; however , disc2 is not conserved among species , hampering investigation of its regulatory mechanisms . one intriguing possibility is the existence of regulatory loop between disc1 and the two ncrna transcripts disc2 and gomafu . recent peripheral blood profiling studies also identified significant disruption of lncrnas in depression , specifically patients with mdd , 17 of which were documented as depression - related gene in previous studies . in parallel , this study uncovered potential mirna - mrna networks that are consistent with genes previously associated with depression . future studies could investigate co - regulatory mechanisms between the dysregulated mirnas and lncrnas in the disease . additionally , the lncrna antisense transcript coded by loc285758 has been implicated in violent suicide completers , likely triggered through depression or other psychiatric disorders . similar to mirnas , it is possible some of the lncrnas listed above may mediate the development of the distinct psychiatric symptoms through control of circadian genes . global transcriptome profiling studies indicate that lncrnas , including nats , epigenetically regulate circadian biology . indeed , an antisense rna to a circadian gene in neurospora , termed qrf , is regulated by light and represses the expression of its sense partner frq , through chromatin modifications . regulating neural plasticity , neurogenesis , and numerous behavioral phenotypes , it is clear that ncrnas contribute to the pathogenesis of many psychiatric disorders . moreover , direct evidence comes from human postmortem brain and animal studies indicating perturbed ncrna levels in disparate disease such as huntington s , schizophrenia , depression , ptsd among others . despite these findings , one needs to find an integrated view of these ncrna network(s ) . it is known that differential co - expression of distinct mirna groups can directly mediate human disease pathogenesis as well as serve as a biomarker profile for disease diagnosis . the disrupted mirnas , and their corresponding mrna target genes in each psychiatric disease , are likely to interact with and regulate each other , both directly as targets and indirectly as part of larger regulatory networks . furthermore , correlated mirnas and mrnas may be coordinately regulated by a ( possibly overlapping ) set of transcription factors or other epigenetic influences . it remains to be determined whether the changes in the mirna / mrna network are i ) similar or different across distinct brain regions ii ) cell type - specific and iii ) reversible mechanisms . the underlying reasons for altered ncrna expression remain unresolved and could result from a number of factors , including genetic changes in the promoter region or other locations within the gene . additionally , defects in rna editing or epigenetic suppression of the chromosomal region encoding the ncrnas can also occur . finally , mirnas , lncrnas , and their processing genes are susceptible to regulation by well - established signaling modulators such as bdnf , creb , calcium , or calcium responsive neurotransmitters . for example , recently it was reported that dicer is activated by proteolytic cleavage under conditions of elevated calcium levels . the networking of mirnas and other ncrnas into critical pathways such as neurotransmission , neurogenesis , and neurodevelopment may open up an entirely new understanding of psychiatric disease . ultimately , we expect that for many of the complex psychiatric disorders we have considered , novel links between ncrna mechanisms and the disease pathology will continue to emerge .