I would like to be able to reopen my brain's critical period of synaptic plasticity for just a short period of time, perform a specific learning task, and then restore it to normal (or not?). Something like taking an autism pill, if you like.
So before even going further, can anyone point me in a sensible direction for this enquiry?
I think studying autism may hold the key to this; I've gotten to know some high functioning autistics / borderline autistics, and what they can do is amazing.
I'm currently reading through a superb article:
Autism: A “Critical Period” Disorder? by Jocelyn J. LeBlanc and Michela Fagiolini
http://www.hindawi.c...np/2011/921680/
Although it is centred around autism, the first part is purely about the critical period of plasticity, and documents different ways to extend it.
I would like to post sections here (annotated by myself), in the hope that the community may connect the various described critical-period-extension-mechanisms with their relevant nootropic compounds.
Ok, here goes!
The paper says that an animal goes through a critical learning phase at the start of its life, in order to create low-level circuits. Then this critical phase is turned off, so that these low-level circuits are stabilised/fixed, and higher-level circuits can make reliable use of them.
It points out that in autistic individuals, this mechanism doesn't kick in. And so they retain low-level plasticity, at the expense of not being able to develop high-level circuits. This simultaneously accounts for their Savant capabilities, and higher-functioning (e.g. emotional) disabilities.
It further goes on to demonstrate this happening with eye-circuits. If one eye is permanently closed, data from the remaining eye will fill out the visual cortex. If the other eye is opened within the critical period, the brain will adapt. But if it is opened afterwards, the brain won't be able to see through that eye. Later on in the paper they will use this particular test as a metric to explore the various techniques of reopening the plasticity critical period.
Interesting, huh?
Ok, now it gets so juicy I'm just going to paste a whole section and intersperse it with comments.
... a specific inhibitory circuit has been identified that controls the timing of OD plasticity [11]. Fine manipulation of inhibitory transmission is difficult in vivo, because enhancing inhibition silences the brain, while reducing inhibition easily induces epilepsy. With the generation of a mouse lacking only one of the two enzymes that synthesizes GABA (GAD65), researchers were able to titrate down the level of inhibition and test its role in the OD critical period [12]. Strikingly, the visual cortex of GAD65 knockout mice remains in an immature, precritical period state throughout life. At any age, functionally enhancing GABAergic transmission with benzodiazepine treatment triggers the opening of a normal-length critical period [72]. Historically, inhibitory neurotransmission was believed to develop postnatally to progressively restrict plasticity, but these key experiments proved GABA to actually be necessary for a normal OD critical period, prompting further investigation into the role of inhibition in brain plasticity.
so, a "GABA inhibitor" to open plasticity, benzodiazepine to close it up again. But how to inhibit GABA synthesis?
Inhibitory interneurons account for nearly 20% of cortical neurons and exhibit heterogeneous morphological and physiological characteristics [73]. Included in this large variety of inhibitory interneurons is a specific subset of GABAergic neurons that expresses the calcium-binding protein parvalbumin. Fast-spiking parvalbumin-positive basket cells (PV-cells) regulate critical period timing and plasticity [11, 74].
So, PV cells inhibit GABA synth. So we want to encourage PV cells.
PV-cells develop with a late postnatal time course in anticipation of critical period onset across brain regions [75, 76]. In the visual cortex, PV-cells mature in an experience-dependent manner, and dark-rearing delays their maturation as well as critical period expression [77, 78]. On the other hand, overexpression of brain-derived neurotrophic factor (BDNF) promotes the maturation of PV-cells and speeds up the onset of the OD critical period [77, 79]. Moreover, Di Cristo et al. [80] have shown that premature cortical removal of polysialic acid (PSA), a carbohydrate polymer presented by the neural cell adhesion molecule (NCAM), results in a precocious maturation of perisomatic innervation of pyramidal cells by PV-cells, enhanced inhibitory synaptic transmission, and an earlier onset of OD plasticity. Recent results indicate that PV-cell maturation is surprisingly regulated by the Otx2 homeoprotein, an essential morphogen for embryonic head formation [78]. Otx2 is stimulated by visual experience to pass from the retina to visual cortex and selectively into PV-cells, thereby promoting their maturation and consequently activating OD critical period onset in the visual cortex.
So BNDF speeds up growth of PV cells. Also removing PSA seems to do the same thing. And Otx2.
What I don't get here is: I think the author is just talking about an infant animal. They don't seem to say anything about whether these mechanisms work on an adult brain.
PV-cells receive direct thalamic input and also connect to each other in large networks across brain regions by chemical synapses and gap junctions [81, 82]. Moreover, PV-cells form numerous synapses onto the somata of pyramidal cells, which in turn enrich these sites with GABAA receptors containing the α1-subunit [11, 70, 74, 78, 83]. This makes PV-cells perfectly situated to detect changes in sensory input, to regulate the spiking of excitatory pyramidal cells, and to synchronize brain regions [84–86]. Manipulations that disrupt this specific circuit will disrupt the OD critical period [87]. Recent studies have made much progress regarding the origin and fate determination of cortical interneurons [88]. In particular, progenitors of PV-cells derive from the medial ganglionic eminence with a relatively late birth date, and their differentiation and migration into specific cortical layers can be regulated by homeoproteins like Lhx6 [88, 89], or excitatory projection neurons [90]. Although the closure of the OD critical period is tightly regulated, transplanting immature GABAergic cells into the visual cortex can reallow OD plasticity later in life [91]. This second sensitive period only emerges once the newly transplanted GABAergic cells reach a critical maturation stage of connectivity. This further supports a key role of inhibition in the timing of experience-dependent circuit refinement.
I don't totally get the first part of this paragraph.
Looks like artificially syringing(?) GABAergic cells into the adult visual cortex reopens plasticity. I wouldn't really want to syringe things into my brain, so the question seems to be: how to encourage GABAergic cells?
Once the critical period is initiated, plasticity is only possible for a set length of time, and then the critical period closes [92]. Several functional and structural brakes on plasticity have been identified in recent years [93]. Disruption of these brakes in the adult brain allows critical periods to reopen and neuronal circuits to be reshaped. In the case of OD plasticity, this means that monocular deprivation in adulthood would induce a shift in responsiveness to the nondeprived eye and cause a loss of acuity in the deprived hemisphere. Interestingly these brakes share a common theme of regulating E/I balance, and particularly the GABAergic system. Locally reducing inhibition in adulthood restores plasticity in visual cortical circuits [94, 95]. Treatment with the antidepressant drug fluoxetine also reopens plasticity, potentially by altering inhibitory transmission and increasing BDNF levels [96, 97]. Finally, knocking out lynx1, an endogenous prototoxin that promotes desensitization of the nicotinic acetylcholine receptor (nAchR), extends the critical period into adulthood [98]. Lynx1 likely modulates E/I balance because treatment with diazepam in lynx1 knockout mice abolishes adult plasticity by restoring this balance to normal adult levels.
My gosh. Steady with the highlighter 
So fluoxetine (TICK). And knocking out lynx1 shortly followed by the word 'nicotinic'... Is this why nicotine is a learning aid? Is this what it is doing?
Structural factors also restrict remodeling of circuits with the closure of critical periods. For example, PV-cells become increasingly enwrapped in perineuronal nets (PNN) of extracellular matrix with the progression of the critical period, and enzymatic removal of these nets or disruption of their formation restores plasticity in adulthood [78, 99, 100]. In addition, the maturation of myelination throughout the layers of the visual cortex, as measured by myelin basic protein (MBP) levels, increases as the critical period closes [101]. Myelin signaling through Nogo receptors (NgRs) limits plasticity in adulthood, and genetic or pharmacological disruption of this receptor allows persistent OD plasticity later in life [101, 102].
Again, Wow! This article is suggesting tons of different techniques for unlocking plasticity.
In addition to reopening plasticity, disruption of these brakes also may allow recovery from early deprivation-induced loss of function, like amblyopia. In order to test this, animals are subjected to long-term monocular deprivation spanning the critical period. This results in permanent amblyopia, even if the deprived eye is reopened in adulthood and allowed to receive visual input. Significantly, some of the manipulations described above allow recovery of acuity, including enzymatic degradation of PNNs [103], disruption of NgR signaling [102], administration of fluoxetine [96], and enhanced cholinergic signaling by lynx1 knockdown or treatment with acetylcholinesterase inhibitors [98]. Treatment with drugs like fluoxetine and acetylcholinesterase inhibitors offers particularly promising therapeutic potential because they are already FDA-approved for human use. As the mechanisms behind the closure of critical periods are explored, more light will be shed on potential interventions that could reopen plasticity or reset abnormal critical periods by restoring the brain to a more juvenile-like state.
Pure gold. Now they have tested out all those various techniques, I guess following the various links would lead to experiments and some kind of idea of the relative effectiveness, safety, side-effects, etc, of the different approaches.
How generally might these same mechanisms apply to critical periods in other parts of the brain? Interestingly, recent evidence has shown that similar mechanisms may exist in other brain regions. For example, the maturation of PV-cells in the barrel cortex peaks during the critical period for whisker tuning [75]. Furthermore, whisker trimming exclusively during this critical period in mice results in decreased PV expression and reduced inhibitory transmission in vitro [104]. In the zebra finch, brain regions dedicated to singing exhibit progressive PNN formation around PV-cells with a time course that parallels the critical period [105]. The maturity of the song correlates with the percentage of PV-cells that are enwrapped in PNNs, and this can be manipulated with experience by altering exposure to tutor song. In rodent auditory cortex, spectrally limited noise exposure prevents the closure of the critical period for regions of auditory cortex that selectively respond to those interrupted frequencies, and PV-cell number is also reduced in those regions [106]. In the rodent, conditioned fear can be eliminated during early life but is protected from erasure in adulthood [57]. A developmental progression of PNN formation around PV-cells coincides with this switch and enzymatic degradation of PNNs allows juvenile-like fear extinction in adulthood [58, 59], similar to the reopening of OD plasticity in the adult visual cortex [99].
While evidence that very distinct critical periods may share a common role for PV-cells and PNNs is promising, such findings are still largely correlative and will require further cellular and molecular dissection in the future. In light of these findings, it is interesting to note that at least nine different mouse models of autism share a common disruption of PV-cells [58, 59]. In relation to what we know about the importance of inhibitory transmission to critical period regulation, it is quite interesting to consider the evidence that inhibition, or E/I balance in general, is disrupted in neurodevelopmental disorders such as autism. A summary of the key evidence supporting the notion of E/I imbalance in autism is presented below.
So they are saying "although we've been focusing on getting a dead-eye back to life, i.e. plasticity in the visual cortex, it stands to reason that the same basic mechanisms are going to work through the whole brain.
I would imagine different areas get switched off at different times, this much may be preprogrammed.
π
