Hippocampal Neurogenesis: Impact on Mood and Cognition
Rene Hen, PhD Departments of Neuroscience and Psychiatry Columbia University “In the adult centers, the nerve paths are something fixed, and immutable; everything may die, nothing may be regenerated” Areas of Adult Neurogenesis In the Human Brain • Why is Adult Neurogenesis Only in the Hippocampus (and Striatum)?
• How Can It Impact Cognition and Mood ? Adult Hippocampal Neurogenesis
CA1 • 3,000 new cells/day • 80% die within 1 month CA3 Mossy Fibers • 70% of surviving ones become mature neurons • All these steps depend DG on the environment Opposite effects of stress and enrichment on neurogenesis
stress normal enriched
Nuclei DCX
Dranovsky et al. 2011 Maturation of adult-born hippocampal neurons
Denny et al. 2011 Outline Adult-born GCs have different properties than mature GCs Unique role in pattern separation Inhibitory effect on mature GCs Distinct context selectivity in vivo Adult-born GCs in the ventral DG influence anxiety-related behaviors Functional map of the hippocampus
Small et al., 2011 Neutral Pattern Separation Task
Stark et al., 2010 The famous Madeleine scene in Marcel Proust’s “A La Recherche du Temps Perdu - Remembrance of Things Past” where eating a Madeleine cookie dipped in a cup of tea causes the narrator to experience a flood of chilhood memories.
"... Suddenly the memory revealed itself. The taste was that of the little piece of madeleine which on Sunday mornings at Combray, when I went to say good morning to her in her bedroom , my aunt Léonie used to give me, dipping it first in her own cup of tea or tisane….. as soon as I had recognized the taste of the piece of madeleine soaked in her decoction of lime-blossom, immediately the old grey house upon the street, where her room was, rose up like a stage and with the house the town, from morning to night and in all weathers, the Square where I used to be sent before lunch, the streets along which I used to run errands….” Emotional pattern separation
BANG
pattern pattern separation completion BANG Impaired pattern separation = generalization PTSD
BANG BANG
Impaired pattern separation may also contribute to the cognitive deficits associated with aging Contextual fear conditioning
Train Test
Freezing A Shock A or Little Freezing B Ablation of hippocampal Neurogenesis
Sham X-ray Neurogenesis is Necessary for Contextual Fear Discrimination Learning
Sahay et al, 2011 Optogenetic control of immature dentate gyrus granule cells
Nestin/Arc
TMX 3mg IP testing
Day1-5 Day 42-49
Kheirbek Inhibition of adult-born GCs during exposure to safe context blocks pattern separation How Can a Small Number of Granule cells Impact The Function of the Whole Hippocampus
Inhibitory effect on mature GCs Distinct context selectivity in vivo Activation of young GCs results in inhibition of mature GCs
abGC matGC GC L P
S
M Hilus
Sham 0 mV
-65 mV * 300 1.0 *** 250 0.8 100 pA 200
0.6 150
0.4 100 *** 0.2 Irradiated 50 PSC Amplitude (pA) Amplitude PSC Proportion Responding Proportion 0.0 0 Sh Ir Sh Ir Sh Ir Sh Ir
IPSC EPSC IPSC EPSC 50 ms Young neurons inhibit mature granule cells
. Drew et al, 2014 A modified treadmill setup for in vivo imaging during contextual learning
Attila Losonczy and lab Imaging adult generated neurons in vivo
NestinCreERT2/Ai9 mouse 6 weeks post TMX
Attila Losonczy
Mazen Kheirbek Spatial tuning of an adult born hippocampal neuron Spatial properties of adult-generated hippocampal neurons
Kheirbek, Losonczy Hippocampus: Learning versus Anxiety/Depression ? Hippocampal Atrophy In Depression And Anxiety Disorders
) Depression 3 2500 Depression
2500
2300
2100
1900 Hippocampal volume (mm 1700 0 1000 2000 3000 4000 Time depressed (days)
Combat stress 12 Combat stress PTSD 10 No PTSD 9
8
7
6 Hippocampal volume (ml) 5 0 10 20 30 40 Months of combat exposure Post traumatic stress disorder Hippocampal Neurogenesis is Required for the Behavioral Effects of Antidepressants
Novelty Suppressed Feeding Chronic Unpredictable Stress
120 120
100 100
80 80 feed ** 60 ** 60 40 40 ** Grooming latencyGrooming latency to latency 20 20
0 0 Veh Flx Imi Veh Flx Imi Veh Flx Veh Flx Sham X-ray Sham X-ray
Santarelli et al, 2003 Dorsal and ventral hippocampus have different functions •Lesion studies: double dissociation between spatial learning and emotional response •Anatomical connections •Physiological studies •Gene expression studies The Rodent Hippocampus: Subregional Specialization dHPC – spatial navigation Entorhinal cortex Perirhinal cortex
Amygdala mPFC BNST Hypothalamus Ventral Striatum vHPC – Anxiety Immature Neurons in Dorsal and Ventral Dentate Gyrus Dorsal DG
Ventral DG
Tau-EGFP under the control of the POMC promoter POMC = proopiomelanocortin. Dorsal and Ventral Irradiation
Wu et al, 2014 Effect of Fluoxetine in NSF is Blocked by Ventral Irradiation
* *
Wu et al, 2014 Hippocampal Neurogenesis in Human Neurogenesis in post mortem samples
A B CA3
GCL CA4 HILUS
500 µm 200 µm
C Nestin-IR Nestin-IR cell density - IRcell density Nestin
Boldrini et al, 2010 Is a stimulation of neurogenesis sufficient to improve pattern separation and decrease anxiety An Inducible Genetic Gain-of-Function Strategy to Increase Adult Neurogenesis
Bax dependent cell death
Nestin
Type I II
X X
*** 3000 Adults 1W 2W 3W 1 M 6 M 1 Y 2500
2000
BrdU S S S S S S 1500
1000
500 Total BrdU+ cells Total 0 1W 2W 3W 1M 6M 1Y Increasing Neurogenesis is Sufficient to Enhance Contextual Discrimination Learning
Sahay et al, 2011 But increased neurogenesis does not affect
mood and anxiety-related behavior
) s Veh Elevated Plus Maze 35 Open Field TAM 40 30
25 30
20
Ce15 ea 20
10 10 5 % Center Distance 0 0 O ( Arms Open in Spent Time
Forced Swim 60 Tail Suspension 200 50 ) ) s s 40 150
30 Ce ea
Cell Mean Cell 100 20 Mobility ( Mobility ( 10 50
0 min 1 min 2 min 3 min 4 min 5 min 6 0 Hill
Genetic stimulation of neurogenesis produces an anxiolytic/antidepressant effect in Cort model
Hill Harnessing neurogenesis to treat anxiety disorders Pharmacologic stimulation of neurogenesis
produces an anxiolytic effect in Cort model
Open Arm Entries Total Arm Entries p = 0.02
4 15
12.5 3
10
2 7.5
5 Open Arm Open Arm Entries 1 2.5
0 0
) s Open Arm Time p = 0.005 Control-Control 30 Control-iMac2 25 Cort-Control
20 Cort-iMac2 15
10
5
0 Time Spent in Open Arms ( Arms Open in Spent Time
Pattern separation is improved by metformin
and running in aged mice
() () 100 100 * * * * 80 80
60 60
Ce ea 40 40 % Time Freezing Time % % Time Freezing Time %
20 old 20 old +met
0 0 d3 d4 d5 d6 d7 d8 d9 d10 d3 d4 d5 d6 d7 d8 d9 d10
() o a s Sta da d o (s) 100 100 * * * * * * * * * * 80 80
60 60
40 40 % Time Freezing Time % 20 old +running Freezing Time % 20 young
0 0
d3 d4 d5 d6 d7 d8 d9 d10 d3 d4 d5 d6 d7 d8 d9 d10 C ll
Translation
Test generalization and pattern separation in patients with anxiety, depression, or age-related memory impairments
Clinical trial with selected compounds targeting the subset of patients who display excessive generalization Why Neurogenesis ? Pattern separation Adaptation to changing environment
How Can It Impact Cognition and Mood ? Dorsal and Ventral Functions Changes in neurogenesis allow adaptation to a changing environment
Environment Neurogenesis Pattern Pattern Adaptative Maladaptative separation completion response response
Enrichment, Exercise, Increased Discrimination, Excessive Learning, neurogenesis Cognitive attention Antidepressants flexibility to details DG/OB CA3/PC Normal
Age-related cognitive Stress, Decreased impairment Aging, Generalization Sensory neurogenesis Anxiety, deprivation PTSD Hen lab
Mazen Lindsay Dan Nesha Melody Wu Kheirbek Tannenholz Costantini Burghardt Eero Castren Liam Drew Ben Amar Suzanne Samuels Sahay Ahmari
Rebecca Alexis Alice Christine Brachman Hill Hu Denny Hen lab Collaborators Liam Drew Amar Sahay Nesha Burghardt Andre Fenton Alexis Hill Maura Boldrini Melody Wu Vicky Arango Ben Samuels Helen Scharfman Mazen Khierbek Attila Losonczy Lindsay Tannenholz Gergely Turi Christine Denny Stefano Fusi Rebecca Brachman Richard Foltin Zoe Donaldson Victor Luna Jessica Jimenez NIMH, NARSAD, NYSTEM, HDRF