Table 2.

A summary of preclinical studies assessing the effects of EE on neuronal plasticity.

Type of EE	EE duration + onset	Species	Outcome	Reference
PREFRONTAL CORTEX
social, toys, wheel	10 weeks from P 21	Rats	no change in dendritic aborization	Kolb et al. 2003
social, toys	60 days from P 21	Rats	mGluRs ↓ IC rats relative to EE or SD; no change in EE	Melendez et al 2004
social	50 days from P 22	Rats	pruning of dendritic length	Himmler et al. 2013
social			dentritic arborization ↓
			cell responsiveness to nicotine ↑
social	20 days from P 21	Hamsters	dentritic arborization ↓	Burleson et al. 2016
social, toys	32–35 days from P 21	Rats	DAT cell surface expression ↓	Zhu et al. 2005
social, toys	70 days from P 21	Rats	does not alter VMAT2 function	Hofford et al. 2014
social, toys	2 months from P 532	Rats	Parvalbumin GABA positive cells ↑	Sampedro-Piquero et al. 2016
social, toys	77 days from P 30	Rats	extracellular 5-HT concentration ↑	Brenes et al. 2008
			no change in extracellular NE concentration
social, toys	21 days from P 30	Rats	c-fos ↑ in PFC and OFC as compared to IC	Sampedro-Piquero et al. 2015
			c-fos ↓ in IFC as compared to IC
social	1 session (15 min) at P 21	Rats	no change in opioid receptor binding	Vanderschuren et al. 1995
social	13 days from P 21	Rats	D2-expressing cells as compared to IC ↓	Han et al 2012
social	9 weeks from P 21	Mice	AMPA (GluR1, 2, 5) expression as compared to IC ↓	Araki et al 2014
social, toys	30 days at P 84	Rats	no change in NE or DA concentration	Galani et al. 2007
			no change in NE or DA concentration
social	8 weeks from P 21	Rats	NMDA NR2A, as compared to IC ↓	Turnock-Jones et al.2009
			no change in NMDA NR1A, NR2B mRNA and protein level
social	9 weeks from P 21	Rats	dendritic aborization and length ↑	Wang et al. 2012
wheel	21 days from P 90	Rats	cocaine-induced cfos ↑	Zlebnik et al. 2014
social, toys	30 days from P 30	Rats	DAT function ↓	Zhu et al. 2004
			DA metabolism ↓
			AMPA pSer845GluA1 expression ↓ (when EE+ extinction training)
social, toys, wheel	32–35 days from P 21	Rats	DAT function ↓ in mPFC but not OFC	Darna et al. 2015
social, toys	2 months from P 21	Mice	no change in FAAH, CB1, MGL mRNA	El Rawas et al. 2011
treadmill	7 days from P 280	Rats	BDNF Activity ↑	Cefis et al. 2019
			BDNFp-TrkB receptors ↑
			synaptophysin (synaptogenesis) ↑
			exercise-induced cfos activation ↑
social	4 sessions (15 min) after cocaine CPP	Rats	no change in cocaine cue-induced fosB	El Rawas er al. 2012
wheel	14 days (2 hrs daily) during forced abstinence	Rats	pERK levels ↓ as compared to sedentary	Lynch et al. 2010
social, toys, wheel	30 days afer cocaine exposure	Mice	cocaine cue-induce cFos activation ↓	Chauvet et al. 2011
social, toys, wheel	6 sessions after cocaine exposure	Rats	AMPA pSer845GluA1 expression ↑ (when EE alone)	Gauthier et al. 2017
social, toys, wheel	31 days during forced abstinence	Rats	cocaine cue induced cfos activation ↓	Thiel et al. 2010
wheel	14 days during forced abstinence + 5 days	Rats	BDNF exon IV expression ↓	Peterson et al. 2014b
wheel	7 or 14 days after cocaine use	Rats	mGlu5 mRNA expression ↑ (with EE during first 7 days)	Abel et al. 2019
			no change in mGlu5 mRNA expression (with EE during last 7 days)
NUCLEUS ACCUMBENS
social, toys, wheel	10 weeks from P 21	Rats	dendritic aborization ↑	Kolb et al. 2003
social	4 sessions (15 min) at P 50–63	Rats	mitogen-activated protein kinase p38 ↓	Salti et al. 2015
social	1 session (15 min) at P 21	Rats	opioid receptor binding ↓	Vanderschuren et al. 1995
social, repeated handling	64 days from P 21	Rats	DA release in response to amphetamine in IC ↑	Hall et al. 1998
			no effect on DA-induced cAMP accumulation D2 inhibition of DA-induced cAMP
			accumulationin IC ↓
social, toys	30 days from P 28	Rats	no change in AMPA GluR1	Wood et al. 2005
			NMDA NR1 ↑ as compared to IC
social	13 days from P 21	Rats	D2-expressing cells as compared to IC ↓	Han et al 2012
social	9 weeks from P 21	Mice	no change in AMPA (GluR1, 2, 5) expression no change in GluR1 Ser845 phosphorylation	Araki et al 2014
social	8 weeks from P 21	Rats	pulse-induced DA release as compared to IC ↓	Karkhanis et al. 2019
			no change in VMAT2, Synaptogyrin-3, Syntaxin-1, Munc13–3 TH expression as compared to IC ↓
social	4 weeks from P 21	Mice	sEPSC and mEPSC, as compared to IC ↓	Zhang et al 2019
			instrinsic excitability of MSNs, as compared to IC ↓
social, toys	77 days from P 30	Rats	no change in extracellular 5-HT	Brenes et al. 2008
			concentration extracellular NE
			concentration ↑
social	8 weeks from P 21	Rats	no change in NMDA receptor mRNA and protein level	Turnock-Jones et al.2009
social	8–9 weeks from P 28	Rats	dendritic length ↑	Wang et al. 2012
wheel	21 days from P 90	Rats	cocaine-induced cfos ↑	Zlebnik et al. 2014
wheel	6 weeks in young adulthood	Rats	Delta-opioid receptor mRNA ↑	Greenwood at al. 2011
			D2 receptors ↓
			no change in kappa-opioid, D1, dynorphin mRNA
			wheel running-induced cfos ↑
treadmill	5 min, 5 days or 6 weeks at P 60	Rats	D1 receptor binding ↓	Robinson et al. 2018
			no change in DAT binding
social, toys	30 days from P 30	Rats	no change inDA clearance/ DAT function	Zhu et al. 2004
social, toys	30 days from P 30	Rats	in NAcore baseline and nicotine DA clearance	Zhu et al. 2013
			nicotine DA clearance ↑ in NA shell but ↓ in NA core
social, toys/ no toys	20 days from P 23	Rats	cocaine-induced DAT protein ↑ in IC, but ↓ in EE	Zakharova et al. 2009
			no change in cocaine-induced DARPP-32
			cocaine-induced TH ↑ in IC, no change in EE
social	4 sessions (15 min) after cocaine CPP	rats	cocaine-induced Zif-268 ↓	Fritz et al. 2011
social, toys, wheel	2–3 months from P 21	Mice	cocaine-induced Zif-268 activation ↓	Solinas et al. 2009
social, toys, wheel	2 months from P 21	Mice	MAP3K12 mRNA expression ↑	Thiriet et al. 2008
			DNM1L mRNA expression ↑
			PKC lambda mRNA expression↑
			DEC mRNA expression ↓
			PSMD4 mRNA expression ↓
social, toys	2 months and during cocaine use from P 21	Rats	PKC signaling ↑	Lichti et al. 2014
			CREB signaling↑
			ERK/ MAPK signaling ↑
			proteins needed for energy production, mRNA splicing, and ubiquitination ↑
			vesiculr glutamate and monoamine transporters expression ↑
social, toys	30 days at P 84	Rats	Serotonin concentration ↓	Galani et al. 2007
			Norepinepherine concentration ↑
			no change in dopamine concentration
social, toys, wheel	6 sessions after cocaine exposure	Rats	no change in AMPA GluA1 or pSer845GluA1 expression	Gauthier et al. 2017
			AMPA pSer845GluA1 expression ↓ (when EE+ extinction training)
social, toys, wheel	2 months from P 21	Mice	cocaine-induced c-Fos activation ↓	Bezard et al. 2003
			BDNF ↑
			no change in D1 or D2 mRNA
social, toys, wheel	30 days afer cocaine exposure	Mice	cocaine cue-induced cFos activation ↓	Chauvet et al. 2011
social, toys	7 days from P 28–30	Rats	Non-CA permeable AMPAR’s ↑	Ma et al. 2016
social, toys, wheel	1, 7 or 30 days	Mice	cocaine cue-induced cFos activation ↓	Solinas et al. 2008
social, toys, wheel	31 days during forced abstinence	Rats	cocaine cue induced cfos activation ↓	Thiel et al. 2010
social, toys, wheel	Rearing (1 month)	Rats	no change in cocaine induced FosB	Zhang et al. 2014
DORSAL STRIATUM
treadmill running	5 min, 5 days or 6 weeks at P60	Rats	D2 receptor-binding ↑	Robinson et al. 2018
			no change in DAT binding
social, toys, wheel	2 months from P 21	Mice	cocaine-induced C-fos mRNA ↑	Bezard et al. 2003
			BDNF ↑
			DAT mRNA and binding ↓
			no change in D1 or D2 mRNA
social, toys, wheel	30 days afer cocaine exposure	Mice	cocaine cue-induced cFos activation ↓	Chauvet et al. 2011
social, toys	30 days from P 30	Rats	no change in DAT function	Zhu et al. 2004
social, toys	70 days from P 21	Rats	no change in DAT function	Hofford et al. 2014
social, toys	2 months from P 21	Mice	no change in FAAH, CB1, MGL mRNA	El Rawas et al. 2011
social	4 sessions (15 min) after cocaine CPP	Rats	no change in cocaine cue-induced fosB activation	El Rawas er al. 2012
social, toys, wheel	31 days during forced abstinence	Rats	no change in cocaine cue-induced cfos activation	Thiel et al. 2010
social, toys, wheel	2–3 months from P 21	Mice	cocaine-induced Delta-Fos B activation ↑	Solinas et al. 2009
AMYGDALA
social	1 session (15 min) at P 21	Rats	no change in opioid receptor binding	Vanderschuren et al. 1995
social	10 sessions with discrete choice trials	Rats	c-fos activation in PKC-expressing inhibitory neurons ↑	Venniro et al. 2018
social	6 weeks from P 21	Rats	DAT ↓ as compared to IC	Karkhanis et al. 2015
		Rats	no change in NET
			alcohol-induced DA release as compared to IC ↑
			alcohol-induced NE release as compared to IC ↓
social	8–9 weeks from P 28	Rats	dendritic aborization and length ↓	Wang et al. 2012
social	4 sessions (15 min) after cocaine CPP	Rats	cocaine-induced Zif-268 activation ↓	Fritz et al. 2011
social, toys	4 sessions (15 min) after cocaine CPP	Rats	cocaine cue-induced fosB activation ↓	El Rawas er al. 2012
			pCREB ↑
social, toys, wheel	30 days afer cocaine exposure	Mice	cocaine cue-induced cFos activation ↓	Chauvet et al. 2011
social, toys	2 months from P 21	Mice	FAAH mRNA ↑	El Rawas et al. 2011
			CB1 mRNA in BLA ↑ but ↓ in BMA
			no change in MGL
social, toys, wheel	6 sessions after cocaine exposure	Rats	no change in AMPA GluA1 or pSer845GluA1 expression	Gauthier et al. 2017
social, toys	4, 15 minute sessions	Rats	zif268 activation ↓ as compared to IC	Zernig and Pinheiro 2015
social, toys	4 sessions (15 min) after cocaine CPP	Rats	no change in cocaine cue-induced fosB	El Rawas er al. 2012
HIPPOCAMPUS
social, toys, wheel	8 weeks from P 21	Mice	morphological changes in astrocytes	Viola et al. 2009
social, toys	4–5 weeks from P 36–45	Rats	synaptic strength ↑	Foster et al. 1996
social, toys, wheel	40 days from P 21	Mice	Neurogenesis ↑	Kempermann et al. 1997
social, toys, wheel	68 days from P 168 or P 504	Mice	Neurogensis ↑	Kempermann et al. 1998
wheel	45 days from P 84 or P 504	Mice	Neurogensis ↑	van Praag et al. 2005
social, toys	34 days from P 50	Rats	BDNF ↑	Fakelnberg et al. 1992
social, toys	6 weeks from P 70	Rats	BDNF ↑	Bakos et al 2009
			glucocorticoid receptor ↓
			no change in AMPA GluR1 and mGluR5
social	9 weeks from P 21	Mice	no change in AMPA (GluR1, 2, 5) expression	Araki et al 2014
			no change in GluR1 Ser845 phosphorylation
wheel	2, 4, 7 nights from P 100	Rats	BDNF ↑	Neeper et al. 1996
			NGF ↑
social, toys	4 weeks from P 25 or 12 weeks from P 145	Rats	Dentritic branching ↑ in adolescents	Fiala et al. 1978
social, toys	90 days from P 25	Rats	Glial Cells ↑	Walsh et al. 1969
			no change in thickness
social, toys	33 days from P 56	Rats	AMPA GluR1 mRNA ↑	Mlynarik et al. 2004
			no change in AMPA NR2A or NR2B
wheel	2 weeks after thiamine deficiency	Rats	Cholinergic functioning ↑	Hall and Savage 2016
			NGF ↑
social, toys, wheel	25 days from P 196	Mice	GAD ↑	Frick et al. 2003
			no change in synaptophysin (synaptogenesis)
social, toys	30 days from P 84	Rats	5-HT concentration ↓	Galani et al. 2007
			NE concentration ↑
			no change in dopamine concentration
social, toys	30 days from P 52	Rats	5-HT1A mRNA and binding ↑	Rasmuson et al. 1998
			no change in 5-HT2A or 5-HT2C receptor mRNA
wheel	1, 3 or 7 days from P 84	Rat	CREB phosphorylation ↑	Shen et al. 2001
			MAPK phosphorylation ↑
social, toys, wheel	30 days afer cocaine exposure	Mice	cocaine cue-induced cFos activation ↓	Chauvet et al. 2011
wheel	21 days concurent with alcohol from P 25	Mice	BDNF mRNA and protein level ↑	Gallego et al. 2015
social, toys, wheel	8 weeks from P 28	Mice	PKA dependent LTP ↑	Duffy et al. 2001
social, toys, wheel/ no wheel	43 days at P 84	Mice	Neurogensis ↑	Brown et al. 2003
treadmill	7 days at P 280	Rats	BDNF Activity ↑	Cefis et al. 2019
			BDNFp-TrkB receptors ↑
			synaptophysin (synaptogenesis) ↑
			exercise-induced cfos activation ↑
social, toys	1 year at P 56	Rats	NGF concentration and NGF receptor density ↑	Pham et al. 1999
social, toys, wheel	40 days from P 28	Mice	AMPA GluR2 and GluR4 mRNA ↑	Naka et al. 2005
social, toys, wheel	8 weeks from P 54 or P 700	Rats	Neurogensis in young rats ↑	Segovia et al. 2006
			Extracellular GABA in old rats ↑
		Rats	Extracellular Glutamate in old rats ↑
social, toys, wheel	59 days from P 35 or P 100	Mice	CREB expression ↑ in young mice	Williams et al. 2001
social, toys, wheel	30 days in adulthood (age not spefiied)	Rats	BDNF expression ↑	Zhang et al. 2016a
			CREB phosphorylation protein expression ↑
			SDF-1 receptor protein expression ↑
			CXCR4 receptor protein expression ↑
			no change in PKA C-alpha protein expression
			Neurogenesis of neurons but not astrocytes ↑
social	3–5 weeks from P 96	Rats	LTP ↑	Artola et al. 2006
			LTD ↑
treadmill	10 days from P 504	Rats	ERK activation ↓	Cardoso et al. 2017
			p38 activation ↓
			no change in Akt, mTOR, pTOS6K, CREB protein expression
social, toys, wheel		Mice	Glutamatergic synapses ↑	Hosseiny et al. 2014
			LTP ↑ (after 8 weeks of EE)
			LTP ↓ (after 4 weeks of EE)
			No change in LTP (after 6 weeks of EE)
social, toys, wheel	6 sessions after cocaine exposure	Rats	no change in AMPA GluA1 or pSer845GluA1 expression	Gauthier et al. 2017
VENTRAL TEGMENTAL AREA
social	1 session (15 min) at P 21	Rats	no change in opioid receptor binding	Vanderschuren et al. 1995
wheel	6 weeks in young adulthood	Rats	TH mRNA ↑	Greenwood at al. 2011
			no change in D2 mRNA
social	4 sessions (15 min) after cocaine CPP	Rats	cocaine-induced Zif-268 activation ↓	Fritz et al. 2011
social, toys	2 months from P 21	Mice	no change in FAAH, CB1, MGL mRNA	El Rawas et al. 2011
social	4 sessions (15 min) after cocaine CPP	Rats	no change in cocaine cue-induced fosB	El Rawas er al. 2012
social, toys, wheel	30 days afer cocaine exposure	Mice	cocaine cue-induce cFos activation ↓	Chauvet et al. 2011
social, toys, wheel	31 days during forced abstinence	Rats	Cue induced cfos activation ↓	Thiel et al. 2010